Pyridin-2(1h)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors

ABSTRACT

The invention relates to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: 
     
       
         
         
             
             
         
       
     
     where A, U, W 1 , W 2 , W 3 , R 1 -R 6 , and R 9  are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/101,018, filed Nov. 23, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/712,951, filed Dec. 12, 2019, now U.S. Pat. No.10,889,567, which is a continuation of Ser. No. 16/290,240, filed Mar.1, 2019, now U.S. Pat. No. 10,550,098, which is a continuation of Ser.No. 15/964,844, filed Apr. 27, 2018, now U.S. Pat. No. 10,414,752, whichis a continuation of Ser. No. 15/452,256, filed Mar. 7, 2017, which is acontinuation of Ser. No. 14/858,167, filed Sep. 18, 2015, now U.S. Pat.No. 9,834,539, which claims the benefit of priority of U.S. ProvisionalApplication No. 62/150,812, filed Apr. 21, 2015, and U.S. ProvisionalApplication No. 62/128,089, filed Mar. 4, 2015, and U.S. ProvisionalApplication No. 62/053,006, filed Sep. 19, 2014, all of which areincorporated herein by reference in their entireties.

FIELD OF INVENTION

The present invention is directed to inhibitors of mutant isocitratedehydrogenase (mt-IDH) proteins with neomorphic activity useful in thetreatment of diseases or disorders associated with such mutant IDHproteins including cell-proliferation disorders and cancers.Specifically, the invention is concerned with compounds and compositionsinhibiting mt-IDH, methods of treating diseases or disorders associatedwith mt-IDH, and methods of synthesis of these compounds.

BACKGROUND OF THE INVENTION

Isocitrate dehydrogenases (IDHs) are enzymes that participate in thecitric acid cycle (cellular metabolism). They catalyze the oxidativedecarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate,α-KG). There are three isoforms within the IDH family. IDH-1, expressedin the cytoplasm and peroxisome, IDH-2, localized in the mitochondria,both utilize NADP+ as the cofactor and exist as homodimers. IDH-3 islocalized in mitochondrial matrix and utilizes NAD+ as a cofactor andexists as tetramer. Mutations in IDH-1 (cytosolic) and IDH-2(mitochondrial) have been identified in various diseases or disordersincluding glioma, glioblastoma multiforme, paraganglioma, supratentorialprimordial neuroectodermal tumors, acute myeloid leukemia (AML),prostate cancer, thyroid cancer, colon cancer, chondrosarcoma,cholangiocarcinoma, peripheral T-cell lymphoma, and melanoma (L. Deng etal., Trends Mol. Med., 2010, 16, 387; T. Shibata et al., Am. J. Pathol.,2011, 178(3), 1395; Gaal et al., J. Clin. Endocrinol. Metab. 2010;Hayden et al., Cell Cycle, 2009; Balss et al., Acta Neuropathol., 2008).The mutations have been found at or near key residues in the activesite: G97D, R100, R132, H133Q, and A134D for IDH1, and R140 and R172 forIDH2. (See L. Deng et al., Nature, 2009, 462, 739; L. Sellner et al.,Eur. J. Haematol., 2011, 85, 457).

Mutant forms of IDH-1 and IDH-2 have been shown to lose wild typeactivity, and instead exhibit a neomorphic activity (also known as again of function activity), of reducing alpha-ketoglutarate to2-hydroxyglutarate (2-HG). (See P. S. Ward et al., Cancer Cell, 2010,17, 225; Zhao et. al., Science 324, 261(2009); Dang et. al Nature 462,739 (2009)). In general, production of 2-HG is enantiospecific,resulting in generation of the D-enantiomer (also known as the Renantiomer or R-2-HG). Normal cells have low basal levels of 2-HG,whereas cells harboring mutations in IDH1 or IDH2 show significantlyelevated levels of 2-HG. High levels of 2-HG have also been detected intumors harboring the mutations. For example, high levels of 2-HG havebeen detected in the plasma of patients with mutant IDH containing AML.(See S. Gross et al., J. Exp. Med., 2010, 207(2), 339). High levels of2-HG have been shown to block α-KG dependent DNA and histonedemethylases, and ultimately to result in improper dedifferentiation ofhematopoietic progenitor cells in AML patients (Wang et. al., Science340, 622 (2013); Losman et al., Science 339, 1621 (2013)).

Furthermore, patients with Oilier Disease and Mafucci Syndrome (two raredisorders that predispose to cartilaginous tumors) have been shown to besomatically mosaic for IDH1 and 2 mutations and exhibit high levels ofD-2-HG. (See Amary et al., Nature Genetics, 2011 and Pansuriya et al.,Nature Genetics, 2011).

The inhibition of mt-IDHs and their neomorphic activity with smallmolecule inhibitors therefore has the potential to be a treatment forcancers and other disorders of cellular proliferation.

SUMMARY OF THE INVENTION

A first aspect of the invention relates to compounds of Formula I:

and pharmaceutical salts, enantiomers, hydrates, solvates, prodrugs,isomers, and tautomers thereof,

wherein:

each W₁ and W₂ is independently CH, CF or N;

W₃ is independently CR₂ or N;

U is N or CR₆;

A is selected from the group consisting of H, D, halogen, CN, —CHO,—COOH, —COOR, —C(O)NH₂, —C(O)NHR, R′S(O)₂—, —O(CH₂)_(n)C(O)R′, R′S(O)—,heteroaryl, —SOMe, —SO₂Me,

wherein X and Y are independently in each occurrence C, N, NR′, S, andO, provided that the ring containing X and Y cannot have more than 4 Nor NH atoms or more than one S or O atoms, and wherein the S and O arenot contiguous;

R and R′ at each occurrence are independently selected from the groupconsisting of H, OH, CN, —CH₂CN, halogen, —NR₇R₈, CHCF₂, CF₃, C₁-C₆alkyl, R₇S(O)₂—, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkylalkyl, 3- to 8-membered heterocyclyl, aryl,and heteroaryl, wherein each R is optionally substituted with one ormore substituents selected from the group consisting of OH, halogen,C₁-C₆ alkoxy, NH₂, R₇S(O)₂—, CN, C₃-C₈ cycloalkyl, 3- to 8-memberedheterocyclyl, aryl, heteroaryl, and R₇S(O)—;

R₁ is independently OH, CN, halogen, CHCF₂, CF₃, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, 3- to 8-memberedheterocyclyl, aryl, or heteroaryl, wherein each C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3- to 8-membered heterocyclyl,aryl, or heteroaryl is optionally substituted one or more times withsubstituents selected from the group consisting of halogen, OH, NH₂, CN,C₁-C₆ alkyl, and C₁-C₆ alkoxy;

each R₂ is independently H, OH, CN, halogen, CF₃, CHF₂, benzyl, C₁-C₆alkyl, C₁-C₆ alkoxy, NH₂, —O(CH₂)_(n)R′, —O(CH₂)_(n)C(O)NHR′,—O(CH₂)_(n)C(O)R′, NHR₇, —N(R₇)(R₈), NHC(O)R₇, NHS(O)R₇, NHS(O)₂R₇,NHC(O)OR₇, NHC(O)NHR₇, —S(O)₂NHR₇, NHC(O)N(R₈)R₇, OCH₂R₇, CHRR′ orOCHR′R₇, wherein C₁-C₆ alkyl, C₁-C₆ alkoxy is optionally substitutedwith one or more substituents selected from the group consisting ofC₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkyl substituted with one or more halogen, 3- to8-membered heterocyclyl, aryl, -heteroaryl-C(O)NH₂, and heteroaryl;

or R₁ and R₂ can combine to form a C₄-C₆ cycloalkyl or a 3- to8-membered heterocyclyl containing at least one atom selected from thegroup consisting of N, O, and S;

R₃ is H, D, C₁-C₆ alkyl, or; —OH;

R₄ and R₅ are independently H, D, halogen, CH₂OH, C₁-C₃ alkyl, or C₁-C₃alkyl substituted with halogen, or R₄ and R₅ when combined can form aC₃-C₆ cycloalkyl or C₃-C₆ heterocyclyl;

each R₆ is H, halogen, C₁-C₆ alkyl, C₁-C₆ alkyl substituted withhalogen, C₁-C₆ alkoxy, C₁-C₆alkoxy substituted with one or more halogen,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3- to 8-memberedheterocyclyl, aryl, or heteroaryl;

R₇ and R₈ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3- to 8-membered heterocyclyl, aryl,and heteroaryl; or when combined R₇ and R₈ can form a 3- to 8-memberedheterocyclyl or heteroaryl ring;

R₉ is independently H, D, CD₃, CF₃, C₁-C₆ alkyl, C₂₋₆ alkenyl, C₃₋₆alkynyl, C₃-C₈ cycloalkyl, wherein the alkyl, alkenyl, alkynyl, andcycloalkyl is optionally substituted with amino, OH, halo, or alkoxy;

n is 0, 1, or 2; and

r is 0, 1, or 2;

with the proviso that when A is H, then R₁ is not C₁-C₆ alkyl or C₁-C₆alkoxy and R₁ and R₂ cannot combine to form a 3- to 8-memberedheterocyclyl.

Another aspect of the invention relates to a method of treating adisease or disorder associated with mutant isocitrate dehydrogenase. Themethod involves administering to a patient in need of a treatment fordiseases or disorders associated with mutant isocitrate dehydrogenase aneffective amount of a compound of Formula I.

Another aspect of the invention is directed to a method inhibitingmutant isocitrate dehydrogenase. The method involves administering to apatient in need thereof an effective amount of the compound of FormulaI.

Another aspect of the invention relates to method of reducing2-hydroxyglutarate. The method comprises administering to a patient inneed thereof an effective amount of the compound of Formula I.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutically acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

The present invention further provides methods of treating cellproliferative diseases and cancers including, without limitation,glioma, glioblastoma multiforme, paraganglioma, supratentorialprimordial neuroectodermal tumors, acute myeloid leukemia (AML),prostate cancer, thyroid cancer, colon cancer, chondrosarcoma,cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepaticcholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS),myeloproliferative disease (MPD), and other solid tumors.

The present invention also provides potent mt-IDH inhibitors withexcellent drug-like properties to cancers and other cell proliferativedisorders. The inhibitors of the present invention may target mutatedIDH1 or IDH2.

The present invention further provides development of potent, orallyactive, and selective IDH inhibitors as therapeutic agents for variousdiseases or disorders including cancers. The invention also providestreatment for solid and hematologic cancers for which there are nocurrently targeted therapies available for patients suffering from theseconditions or disorders.

BRIEF DESCRIPTION OF THE DRAWINGS OF THE INVENTION

FIG. 1 illustrates a graph showing the potency of IDH1 inhibitors inIDH1-R132H Enzymatic Assay using compounds I-1, I-5, and I-20.

DETAILED DESCRIPTION OF THE INVENTION

IDH1 or IDH2 mutations are a genetically validated target in many solidand hematologic cancers, but there are currently no targeted therapiesavailable for patients in need of treatment for specific conditionsassociated with mt-IDH activity. Non-mutant IDH (e.g., wild-type)catalyze the oxidative decarboxylation of isocitrate to α-ketoglutaratethereby reducing NAD⁺ (NADP⁺) to NADH (NADPH) (WO 2013/102431 toCianchetta et al., hereby incorporated by reference in its entirety).Mutations of IDH present in certain cancer cells result in a new abilityof the enzyme to catalyze the NADPH-dependent reduction ofα-ketoglutarate R(−)-2-hydroxyglutarate (2HG). 2HG is not formed bywild-type IDH. The production of 2HG contributes to the formation andprogression of cancer (Dang, L et al., Nature, 2009, 462:739-44, herebyincorporated by reference in its entirety). The present inventionprovides inhibitors of mt-IDH, and prophylactic measures to reduce theformation and progression of 2HG in cells.

In a first aspect of the invention, are described the compounds ofFormula I:

and pharmaceutically acceptable salts, enantiomers, hydrates, solvates,prodrugs, isomers, and tautomers thereof, where A, U, W₁, W₂, W₃, R₁-R₆,and R₉ are as described above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, CN, —COOH, —CH₂CN,—O—C₁-C₆alkyl, C₁-C₆alkyl, —OC₁-C₆alkenyl, —OC₁-C₆alkynyl,—C₁-C₆alkenyl, —C₁-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —OC(O)OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂,—NHC(O)C₁-C₆alkyl, —C(O)NHC₁-C₆alkyl, —S(O)₂—C₁-C₆alkyl,—S(O)NHC₁-C₆alkyl, and S(O)N(C₁-C₆alkyl)₂

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 2 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—C₁-C₆alkyl, C₁-C₆alkyl, —OC₁-C₆alkenyl, —OC₁-C₆alkynyl,—C₁-C₆alkenyl, —C₁-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl,—C(O)C₁-C₆alkyl, —OC(O)OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂,—S(O)₂—C₁-C₆alkyl, —S(O)NHC₁-C₆alkyl, and S(O)N(C₁-C₆alkyl)₂. Thesubstituents can themselves be optionally substituted. Furthermore whencontaining two fused rings the aryl groups herein defined may have anunsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these aryl groups include indanyl,indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 10 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl,and derivatives thereof. Furthermore when containing two fused rings thearyl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine, and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine and iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a C₁-C₆ alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain.Examples of alkoxy groups include without limitation, methoxy, ethoxy,propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. Examples of alkenyl groups include ethenyl,propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18carbon atoms. Examples of cycloalkyl groups include, withoutlimitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Cycloalkylalkyl” means monocyclic saturated carbon rings containing3-18 carbon atoms further substituted with C₁-C₆ alkyl groups. Ingeneral cycloalkylalkyl groups herein described display the followingFormula

where m is an integer from 1 to 6 and n is an integer from 1 to 16.

“Heterocyclyl” or “heterocycloalkyl” monocyclic rings containing carbonand heteroatoms taken from oxygen, nitrogen, or sulfur and wherein thereis not delocalized n electrons (aromaticity) shared among the ringcarbon or heteroatoms; heterocyclyl rings include, but are not limitedto, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.In accordance with the present invention, 3- to 8-membered heterocyclylrefers to saturated or partially saturated non aromatic rings structurescontaining between 3 and 8 atoms in which there is at least oneheteroatoms selected from the group N, O, or S.

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

In one embodiment of the invention, A is CN. In this embodiment, R₉ mayfurther be H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl. In another embodiment, R₉may also be methyl or Ethyl.

In another embodiment of the compounds of Formula I, U is N. In thisembodiment, A may further be CN.

In other embodiments of the invention, are describe the compounds ofFormula I where A is H or F.

In other embodiments of the invention, are describe the compounds ofFormula I where A is

Another embodiment of the invention pertains to compounds of Formula Iwhere R₄ and R₅ are H.

In another embodiment of the invention, R₃ is H, methyl or ethyl.

In another embodiment of the compounds of Formula I, R₄ is H and R₅ ismethyl.

In yet another embodiment of the invention, R₄ is H and R₅ is(S)-methyl.

In another embodiment, R₄ and R₅ are halogen.

In another embodiment of the compounds of Formula I, R₄ is F and R₅ ismethyl.

In another embodiment, R₄ and R₅ can combine to form a C₃-C₆ cycloalkyl.

In one embodiment of the compounds of Formula I, W₁, W₂, and W₃ are allCH.

In one embodiment of the compounds of Formula I, W₁, W₂, or W₃ are CF.

In one embodiment, W₁ or W₃ is CH or N.

In one embodiment, W₃ is CR₂.

In another embodiment of the invention, R₁ can be halogen. In anotherembodiment, R₁ is chloro.

In one embodiment of the invention R₂ can be H, halogen, or C₁-C₆alkoxy. In another embodiment, R₂ can also be C₁-C₆ alkoxy substitutedwith heteroaryl or 3- to 8-membered heterocyclyl.

In another embodiment, illustrative compounds of Formula I are:

-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   6-chloro-3-{[(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   6-chloro-3-{[(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   3-{[(6-bromo-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   6-chloro-3-({[1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl]amino}methyl)-1,2-dihydroquinolin-2-one;-   methyl    5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-6-oxo-1,6-dihydropyridine-3-carboxylate;-   6-chloro-7-methoxy-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;-   6-chloro-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-2-one;-   5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyrazine-2-carbonitrile;-   5-{[(1R)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1R)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1R)-1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-({1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl}amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-{6-chloro-2-oxo-7-[(1R)-1-(pyridin-2-yl)ethoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-[6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-[(1-{6-chloro-7-[(3,3-difluorocyclobutyl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}ethyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-[6-chloro-2-oxo-7-(propan-2-yloxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1R)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;    and-   5-{[(1S)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile.

In another embodiment, illustrative compounds of Formula I include:

-   5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1-(trifluoromethyl)-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-[6-chloro-7-(2-hydroxypropan-2-yl)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{1[(1S)-1-(6-chloro-7-cyclopropyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-(6-chloro-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-{6-chloro-7-[(2-hydroxy-2-methylpropyl)amino]-2-oxo-1,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-[7-(azetidin-1-yl)-6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-[7-(azetidin-1-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   5-{[(1S)-1-[6-chloro-7-(3,3-difluoroazetidin-1-yl)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;-   6-chloro-3-[(1S)-1-{[1-methyl-2-oxo-6-(1H-1,2,3,4-tetrazol-1-yl)-1,2-dihydropyridin-3-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;    and-   5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide.

In one embodiment, the compounds of the invention have the Formula Ia:

In another embodiment, the compounds of the invention have the FormulaIa-1:

In another embodiment, the compounds of the invention have the FormulaIa-2:

In another embodiment, the compounds of the invention have the FormulaIb:

In another embodiment, the compounds of the invention have the FormulaIb-1:

In another embodiment of the invention, the compounds of Formula I areenantiomers. In some embodiments the compounds are (S)-enantiomer. Inother embodiments the compounds may also be (R)-enantiomer. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.

In another embodiment of the invention, the compounds of Formula Icontain isotopes of atoms forming the structure of Formula I. Isotopesherein means, each of two or more forms of the same element (e.g., H andD; ¹²C and ¹³C) that contain equal numbers of protons but differentnumbers of neutrons in their nuclei, and hence differ in relative atomicmass.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis or trans configuration. All tautomeric formsare also intended to be included.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating adisease or disorder associated with mutant isocitrate dehydrogenase. Themethod involves administering to a patient in need of a treatment fordiseases or disorders associated with mutant isocitrate dehydrogenase aneffective amount of the compositions and compounds of Formula I.

Another aspect of the invention is directed to a method inhibitingmutant isocitrate dehydrogenase. The method involves administering to apatient in need thereof an effective amount of the compositions orcompounds of Formula I.

Examples of a mutant IDH protein having a neomorphic activity are mutantIDH1 and mutant IDH2. A neomorphic activity associated with mutant IDH1and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HGneomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity).Mutations in IDH 1 associated with 2-HG neomorphic activity,specifically R-2-HG neomorphic activity, include mutations at residues97, 100, and 132, e.g. G97D, R100Q, R132H, R132C, R132S, R132G, R132L,and R132V. Mutations in IDH2 associated with 2-HG neoactivity,specifically R-2-HG neomorphic activity, include mutations at residues140 and 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.

Another aspect of the invention relates to method of reducing2-hydroxyglutarate. The method comprises administering to a patient inneed thereof an effective amount of the compositions or compounds ofFormula I.

One therapeutic use of the compounds or compositions of the presentinvention which inhibit mt-IDH is to provide treatment to patients orsubjects suffering from cell proliferative diseases and cancersincluding, without limitation, glioma, glioblastoma multiforme,paraganglioma, supratentorial primordial neuroectodermal tumors, acutemyeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer,chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma,melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplasticsyndrome (MDS), myeloproliferative disease (MPD), and other solidtumors. Targeted treatments for these cancers and cell proliferativediseases are not currently available to patients suffering from theseconditions. Therefore, there is a need for new therapeutic agentsselective to these conditions.

The disclosed compounds of the invention can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algiic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds ofFormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present invention includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent invention Formula (I) can be synthesized by following the stepsoutlined in Schemes 1-2, which comprise different sequences ofassembling intermediates II, III, IV, and V. Starting materials areeither commercially available or made by known procedures in thereported literature or as illustrated.

wherein A, U, W₁, W₂, W₃, R₁-R₉ are defined in Formula (I).

The general ways of preparing target molecules of Formula I by usingintermediates II, III, IV, and V are outlined in Scheme 1 and 2.Displacement of aryl halides (III) with intermediates amine (II) understandard nucleophilic substitution conditions using base such asN,N-diisopropylethylamine, and/or potassium carbonate, cesium carbonatein solvent DMSO or DMF gives the compounds of Formula I. Reductiveamination of aldehyde (IV) with amine (V) is performed under standardprocedure (AcOH and NaBH(OAc)₃) to prepare the compound of Formula I(where R₄=R₅═H). A mixture of enantiomers, diastereomers, cis/transisomers resulted from the process can be separated into their singlecomponents by chiral salt technique, chromatography using normal phase,reverse phase or chiral column, depending on the nature of theseparation.

It should be understood that in the description and formulae shownabove, the various groups A, U, W₁, W₂, W₃, R₁-R₆, and R₉ and othervariables are as defined above, except where otherwise indicated.Furthermore, for synthetic purposes, the compounds of schemes 1 and 2are mere representative with elected radicals to illustrate the generalsynthetic methodology of the compound of Formula I as defined herein.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Table 6 provides activity of illustrative compounds of Formula I inIDH1-R132H, IDH1-R132C, IDH1-MS-HTC116-R132H, and IDH1-MS-HTC116-R132Cassays.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker or Varian spectrometers at 300 MHz.Spectra are given in ppm (δ) and coupling constants, J, are reported inHertz. Tetramethylsilane (TMS) was used as an internal standard. Massspectra were collected using a Waters ZQ Single Quad Mass Spectrometer(ion trap electrospray ionization (ESI)). High performance liquidchromatograph (HPLC) analyses were obtained using a XBridge Phenyl orC18 column (5 μm, 50×4.6 mm, 150×4.6 mm or 250×4.6 mm) with UV detection(Waters 996 PDA) at 254 nm or 223 nm using a standard solvent gradientprogram (Method 1-4).

LCMS Method 1 (ESI, 4 Min Method):

Instruments: HPLC: Waters HT2790 Alliance MS: Waters ZQ Single UV:Waters 996 PDA Quad Mass Spectrometer Conditions: Mobile phase A 95%water/5% methanol with 0.1% Formic Acid Mobile phase B (B) 95%methanol/5% water with 0.1% Formic Acid Column XBridge Phenyl or C18, 5μm 4.6 × 50 mm Column temperature Ambient LC gradient Linear 5-95% B in2.5 min, hold 95% B to 3.5 min LC Flow rate 3 mL/min UV wavelength 220nm and 254 nm Ionization Mode Electrospray Ionization; positive/negative

LCMS Method 2 (ESI, 10 Min Method):

Instruments: HPLC: Waters HT2790 Alliance MS: Waters ZQ Single UV:Waters 996 PDA Quad Mass Spectrometer Conditions: Mobile phase A (A) 95%water/5% methanol with 0.1% Formic Acid Mobile phase B (B) 95%methanol/5% water with 0.1% Formic Acid Column XBridge C18, 5 μm 4.6 ×150 mm Column temperature Ambient LC gradient Linear 5-95% B in 5.5 min,hold 95% B to 7.5 min LC Flow rate 1.2 mL/min UV wavelength 220 nm and254 nm Ionization Mode Electrospray Ionization; positive/negative

LCMS Method 3: (APCI, 20 Min) Instruments and Conditions:

HPLC-Agilent 1100 series.Column: Agela Technologies Durashell C18, 3 μm, 4.6×50 mm,).

Mobile Phase A: ACN+0.1% TFA. Mobile Phase B: Water+0.1% TFA.

Gradient: Time (min) % B

00 95 15 05 18 05 20 95Flow Rate: 1 mL/min.

Column Temperature: Ambient. Detector: 254 nm. LCMS Method 4 (ESI, 2.5Min Method):

Instruments and conditions: HPLC: Waters Acquity Binary Solvent ManagerMS: Waters ZQ Mass Detector UV: Waters Acquity PDA Mobile phase A (A)95% water/5% acetonitrile with 0.1% formic acid in 10 mM ammoniumformate Mobile phase B (B) 95% acetonitrile/5% water with 0.09% formicacid Column Waters Acquity UPLC BEH C18, 1.7 μm, 2.1 × 50 mm Columntemperature 35° C. LC gradient 5-100% B in 2.0 min, hold 100% B to 2.2min LC Flow rate 0.6 mL/min UV wavelength 220 nm and 254 nm IonizationMode Electrospray Ionization; positive/negative

Abbreviations Used in the Following Examples and Elsewhere Herein are

-   Ac₂O acetic anhydride-   ACN Acetonitrile-   BOP ammonium 4-(3-(pyridin-3-ylmethyl)ureido)benzenesulfinate-   CDCl₃ deuterated chloroform-   Cs₂CO₃ cesium carbonate CuSO₄ copper sulfate-   δ chemical shift-   DCM dichloromethane or methylene chloride-   DCE 1,2-dichloroethane-   DEAD diethyl azodicarboxylate-   DIAD diisopropyl azodicarboxylate-   DIEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DME dimethoxyethane-   DMF N,N-dimethylformamide-   DMP Dess-Martin Periodinane-   DMSO dimethylsulfoxide-   DMSO-d₆ deuterated dimethylsulfoxide-   dppf 1,1′-Bis(diphenylphosphino)ferrocene-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   ee enantiomeric excess-   EtOAc ethyl acetate-   EtOH ethanol-   ¹H NMR proton nuclear magnetic resonance-   HOAc acetic acid-   HATU    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate-   HCl hydrochloric acid-   HOBT 1H-benzo[d][1,2,3]triazol-1-ol hydrate-   HPLC high pressure liquid chromatography-   Hz hertz-   IPA isopropyl alcohol-   KOAc potassium acetate-   K₂CO₃ potassium carbonate-   LAH lithium aluminum hydride-   LCMS liquid chromatography/mass spectrometry-   (M+1) mass+1-   m-CPBA m-chloroperbenzoic acid-   MeOH methanol-   MeMgBr methyl magnesium bromide-   MS mass spectrometry-   NaBH₄ sodium borohydride-   Na₂SO₄ sodium sulfate-   Pd(dppf)Cl₂    [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Palladium tetrakis Tetrakis(triphenylphosphine)palladium(0)-   Rt retention time-   TBDMS-Cl Tert-butyl dimethylsilyl chloride-   TEA triethylamine-   THF tetrahydrofuran-   TLC thin layer chromatography-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Example 1—Intermediate II-1:(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride

Step-1:(R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (15.0 g, 66.37mmol) and (R)-2-methylpropane-2-sulfinamide (8.85 g, 73.14 mmol) in1,2-dichloroethane (150 mL) was added CuSO₄ (16.0 g, 100.25 mmol). Theresulting mixture was heated to 55° C. and stirred at 55° C. overnight.After TLC and MS showed complete disappearance of starting materials,the mixture was cooled to room temperature and filtered through a pad ofCelite®. The pad of celite was then rinsed with CH₂Cl₂. The filtrate wasevaporated to dryness in vacuo and purified by SiO₂ columnchromatography (0 to 25% hexanes/EtOAc) to afford the title compound,(R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide,as a yellow solid (17.7 g, 81% yield).

Step-2:(R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(8.85 g, 26.88 mmol) in anhydrous CH₂Cl₂ (200 mL) at −60° C. was addeddropwise MeMgBr (3M solution in diethyl ether, 13.5 mL, 40.54 mmol). Theresulting reaction mixture was stirred at about −60 to −50° C. for 3hours and then stirred at −20° C. overnight under an atmosphere of N₂.After TLC and MS showed complete disappearance of starting materials,saturated NH₄Cl (163 mL) was added at −20° C. and the resulting mixturewas stirred for 10 minutes. The aqueous phase was extracted with CH₂Cl₂(100 mL×3), dried over anhydrous Na₂SO₄, filtered, and evaporated. Theresidue was purified by column chromatography on an ISCO® chromatographysystem (SiO₂: Gold column; gradient; hexanes to 100% EtOAc) to providethe title compound,(R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide,as a yellow solid (5.8 g, 63% yield).

Step-3: (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride(II-1)

A mixture of(R)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(6.6 g, 19.13 mmol) in 1,4-dioxane (41 mL) and 1N HCl (41 mL) was heatedat reflux overnight. The solvents were evaporated in vacuo and theresulting residue was dissolved in hot water and lyophilized. The crudeproduct was triturated with diethyl ether to afford the title compoundII-1 as a yellow solid (9.0 g, ee: 98.4%). ¹H NMR (300 MHz, DMSO-d₆): δppm 12.4 (br s, 1H), 8.32 (br s, 2H), 8.07 (s, 1H), 7.85 (d, J=2.2 Hz,1H), 7.63 (dd, J₁=8.8 Hz, J₂=2.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H),4.40-4.45 (m, 1H), 1.53 (d, J=8.5 Hz, 3H). LCMS (Method 3): Rt 3.42 min,m/z 223.1 [M+H]⁺.

Example 2—Intermediate II-2:(R)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride

Step-1:(R)—N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (500 mg, 2.21 mmol)and (R)-2-methylpropane-2-sulfinamide (295 g, 2.43 mmol) in1,2-dichloroethane (15 mL) was added CuSO₄ (530 mg, 3.31 mmol). Theresulting mixture was heated to 55° C. and stirred at 55° C. for 18hours. Once TLC and MS showed complete disappearance of startingmaterials, the reaction mixture was cooled to room temperature andfiltered through a pad of Celite®. The pad of celite was then rinsedwith CH₂Cl₂. The filtrate was evaporated to dryness in vacuo andpurified by column chromatography on an ISCO® chromatography system(SiO₂; hexanes to 60% EtOAc/hexanes) to afford the title compound,(R)—N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide,as a yellow solid (510 mg, 70% yield).

Step-2:(R)—N—((R)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R)—N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(505 mg, 1.534 mmol) in anhydrous THF (8 mL) at 0° C. was added dropwiseMeMgBr (3M solution in diethyl ether, 0.56 mL, 1.687 mmol). The mixturewas stirred at 0° C. for 3 hours under an atmosphere of N₂. After TLCand MS showed complete disappearance of starting materials, saturatedNH₄Cl (5 mL) was added at 0° C. and the resulting mixture was stirredfor 10 minutes. The aqueous phase was extracted with EtOAc (10 mL×3),dried over anhydrous Na₂SO₄, filtered, and evaporated. The residue waspurified by column chromatography on an ISCO® chromatography system(SiO₂; hexanes to 80% EtOAc/hexanes) to afford the title compound as theR,R isomer as a pale yellow solid (200 mg, 38%) and the R,S isomer as apale yellow solid (93 mg, 18% yield).

Step-3: (R)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride(II-2)

A mixture of(R)—N—((R)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(190 mg, 0.55 mmol) in 1,4-dioxane (2 mL) and 1N HCl (1.1 mL, 1.1 mmol)was heated to 150° C. for 30 minutes in a microwave reactor. Thesolvents were evaporated and the residue was dissolved in hot water andlyophilized to afford the title compound II-2 as a yellow solid (148 mg,quantitative yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.35 (br s, 1H),8.28 (br s, 2H), 8.05 (s, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.63 (dd, J=8.8Hz, J₂=2.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.40-4.45 (m, 1H), 1.53 (d,J=8.5 Hz, 3H). LCMS (Method 3): Rt 3.40 min, m/z 223.1 [M+H]⁺.

Example 3—an Alternative Approach to Intermediate II-1

Step-1: 3-acetyl-6-chloroquinolin-2(1H)-one

A mixture of 2-amino-5-chlorobenzaldehyde (0.5 g, 3.21 mmol) and2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.594 g, 4.18 mmol) in xylenes (10mL) under an atmosphere of nitrogen was heated to reflux for 3 hours andthen cooled to room temperature. The reaction mixture was filtered andwashed with xylenes twice to afford the title compound,3-acetyl-6-chloroquinolin-2(1H)-one (330 mg, 46.3%). ¹H NMR (300 MHz,DMSO-d₆): δ ppm 12.22 (br, 1H), 8.41 (s, 2H), 8.00 (s, 1H), 7.63 (d,J=8.8 Hz, 1H), 7.32 (dd, J=8.8 Hz, J₂=2.5 Hz, 1H), 2.58 (s, 3H). LCMS(Method 1): m/z 222.94 [M+H]⁺.

Step-2:((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of tetraethoxytitanium (144 mg, 0.632 mmol),(S)-2-methylpropane-2-sulfinamide (38.3 mg, 0.316 mmol), and3-acetyl-6-chloroquinolin-2(1H)-one (70 mg, 0.316 mmol) in THF (20 mL)was heated to 80° C. overnight and then cooled to room temperature. Tothis mixture was added NaBH₄ (59.7 mg, 1.579 mmol) at −50° C. Themixture was then slowly warmed up to room temperature overnight. MeOH (2mL) was added to quench excess NaBH₄ and was followed by the addition ofwater. The resulting mixture was filtered to remove solids and theaqueous phase was extracted with EtOAc twice, dried over Na₂SO₄ andconcentrated. The residue was purified on a Biotage® chromatographysystem using a 25 g SiO₂ column with gradient elution (20% to 100%EtOAc/Hexanes, then 0-5% MeOH/DCM) to afford(S)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(39 mg, 38% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.05 (br, 1H),7.95 (s, 1H), 7.84 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 5.76 (d, J=8.06 Hz,1H), 5.37 (m, 1H), 4.55 (m, 1H), 1.44 (d, J=6.82 Hz, 3H), 1.18 (s, 9H).LCMS (Method 1): Rt 2.22 min; m/z 327.96 [M+H]⁺.

Step-3: (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride(II-1)

To a solution of((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 0.459 mmol) in MeOH (5 mL) was added HCl(2 mL, 8.0 mmol, 4M in 1,4-dioxane). The mixture was stirred at roomtemperature overnight. To this mixture was added 6 mL of ethyl ether andthe resulting precipitate was collected by filtration, washed with ethylether (2×), and then dried to afford(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride (50 mg,42% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.4 (br s, 1H), 8.32 (brs, 2H), 8.07 (s, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.63 (dd, J₁=8.8 Hz,J₂=2.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.40-4.45 (m, 1H), 1.53 (d,J=8.5 Hz, 3H). LCMS (Method 1): Rt 1.22 min, m/z 223.1 [M+H]⁺. Theenantiomer purity (ee %) of II-1 (>98%) was determined by chiral HPLCanalysis.

Example 4—Alternate approach(R)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride (II-2)

Step-1:((R)—N—((R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of tetraethoxytitanium (412 mg, 1.805 mmol)(R)-2-methylpropane-2-sulfinamide (131 mg, 1.083 mmol) and3-acetyl-6-chloroquinolin-2(1H)-one (160 mg, 0.722 mmol) in THF (20 mL)was heated to 80° C. overnight, then cooled to room temperature. To thismixture was added NaBH₄ (137 mg, 3.61 mmol) −50° C. The mixture was thenslowly warmed up to room temperature overnight. MeOH (2 mL) was added toquench excess NaBH₄ and was followed by the addition of water. Theresulting mixture was filtered to remove solids and the aqueous phasewas extracted with EtOAc twice, dried over Na₂SO₄ and concentrated. Theresidue was purified on a Biotage® chromatography system using a 25 gSiO₂ column with gradient elution (20 to 100% EtOAc/Hexanes, then 0-5%MeOH/DCM) to afford((R)—N—((R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (157 mg, 66% yield). ¹H NMR (300 MHz, CDCl₃): δppm 11.31 (br, 1H), 7.35 (s, 1H), 7.07-7.22 (m, 2H), 5.86 (d, J=9.3 Hz,1H), 5.37 (m, 1H), 4.55 (m, 1H), 1.56 (d, J=6.94 Hz, 3H), 1.32 (s, 9H).LCMS (Method 1): Rt 2.20 min, m/z 327.96 [M+H]⁺.

Step-2: (R)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride(II-2)

To a solution of(R)—N—((R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(150 mg, 0.459 mmol) in MeOH (5 mL) was added HCl (2 mL, 8.00 mmol, 4Min 1,4-dioxane) The mixture was stirred at room temperature overnight.To this mixture was added 6 mL of ethyl ether and the resultingprecipitate was collected by filtration, washed with ethyl ether (2×),and then dried to afford (R)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride (80 mg, 67% yield). ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.32(br s, 1H), 8.34 (br, 2H), 8.06 (s, 1H), 7.81 (s, 1H), 7.58 (d, J=8.82Hz, 1H), 7.31 (d, J=8.83 Hz, 1H), 4.40-4.45 (m, 1H), 1.53 (d, J=6.81 Hz,3H). LCMS (Method 1): Rt 1.20 min, m/z 223.1 [M+H]⁺. The enantiomerpurity (ee %) of II-2 (>98%) was determined by chiral HPLC analysis.

Example 5—Intermediate II-3:(S)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one

Step-1: N-(4-chloro-3-fluorophenyl)acetamide

To a solution of 4-chloro-3-fluoroaniline (10.00 g, 68.7 mmol) and DIEA(13.2 mL, 76 mmol) in EtOAc (200 mL) was added Ac₂O (7.1 mL, 75 mmol)dropwise The solution was stirred at room temperature overnight. OnceLCMS indicated the reaction had gone to completion, the solution waswashed with water (2×100 mL) and brine (100 mL), dried (Na₂SO₄),filtered, and evaporated under reduced pressure to provide the productas a white solid. LCMS and ¹H NMR are consistent withN-(4-chloro-3-fluorophenyl)acetamide (12.39 g, 66.0 mmol, 96% yield)¹HNMR (300 MHz, DMSO-d₆): δ ppm 10.26 (s, 1H), 7.77 (dd, J=12.17, 2.20 Hz,1H), 7.49 (dd, J=8.60, 8.60 Hz, 1H), 7.30 (dd, J=8.79, 2.35 Hz, 1H),2.06 (s, 3H). LCMS (Method 1): m/z 188 [M+H]⁺.

Step-2: 2,6-dichloro-7-fluoroquinoline-3-carbaldehyde

A tube was capped with a septum and placed under an atmosphere ofnitrogen. DMF (9.5 mL, 123 mmol) was added by syringe and then cooled onan ice bath. POCl₃ (37 mL, 397 mmol) was added dropwise by syringe (over25 minutes). The red solution was allowed to warm to room temperature(over 20 minutes), then the septum was removed and the mixture wastreated with N-(4-chloro-3-fluorophenyl)acetamide (7.00 g, 37.3 mmol)The tube was then sealed and the solution was stirred at 80° C.overnight. The solution was pipetted onto ice, resulting in formation ofa yellow precipitate. The precipitate was collected on a Buchner funneland washed with water (500 mL), during which most of the precipitatedissolved. The filter cake was dried to provide 427.6 mg of the titlecompound as a pale yellow solid. LCMS and ¹H NMR are consistent withimpure 2,6-dichloro-7-fluoroquinoline-3-carbaldehyde (427.6 mg, 1.752mmol, 4.70% yield) The material was used without further purification.¹H NMR (300 MHz, DMSO-d₆): δ ppm 10.36 (s, 1H), 8.99 (s, 1H), 8.67 (d,J=8.21 Hz, 1H), 8.13 (d, J=10.26 Hz, 1H), 5.76 (s, 1H). LCMS (Method 1):m/z 244 [M+H]⁺.

Step-3:N-((2,6-dichloro-7-fluoroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of 2,6-dichloro-7-fluoroquinoline-3-carbaldehyde (424.4 mg,1.739 mmol) and 2-methylpropane-2-sulfinamide (253.8 mg, 2.094 mmol) wasplaced under an atmosphere of nitrogen. THF (4 mL) and titanium (IV)isopropoxide (Ti(O^(i)Pr)₄) (1.00 mL, 3.41 mmol) were then added bysyringe and the resulting suspension was stirred at room temperature for48 hours. Once LCMS indicated the reaction had gone cleanly tocompletion. The reaction was quenched by dropwise addition of aqueoussaturated NH₄Cl (2 mL). The mixture was triturated with EtOAc (100 mL),and the solid was collected on a Buchner funnel, and was washed withEtOAc (50 mL). The filtrate was washed with brine (50 mL), dried(Na₂SO₄), filtered, and evaporated under reduced pressure to provide574.3 mg of the title compound as a yellow solid. LCMS and ¹H NMR areconsistent with(E)-N-((2,6-dichloro-7-fluoroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(574.3 mg, 1.654 mmol, 95% yield)¹H NMR (300 MHz, DMSO-d6): δ ppm 9.13(s, 1H), 8.87 (s, 1H), 8.67 (d, J=8.21 Hz, 1H), 8.11 (d, J=10.26 Hz,1H), 1.25 (s, 9H). LCMS (Method 1): m/z 347 [M+H]⁺.

Step-4:N-(1-(2,6-dichloro-7-fluoroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

N-((2,6-dichloro-7-fluoroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(573.6 mg, 1.652 mmol) was placed in a 100 mL round-bottom flask underan atmosphere of nitrogen. DCM (14 mL) was added and the resultingsuspension was cooled in a dry ice/chloroform bath (to approx. −60° C.).Methyl magnesium bromide (MeMgBr) (3M in ethyl ether, 0.83 mL, 2.490mmol) was then added dropwise. The reaction was stirred at −60° C. forseveral hours, and then at −20° C. overnight. The mixture was placed inan ice bath and treated dropwise with water (7 mL). The mixture wasdiluted with water (150 mL) and extracted with EtOAc (3×50 mL). Silicagel was added to the combined extracts and the sample was evaporatedunder reduced pressure. The sample was purified by column chromatographyon a Biotage® MPLC chromatography system (eluted with 0 to 100% EtOAc inhexanes and with isocratic elution when peaks eluted) to provide 226.3mg of the title compound as a yellowish solid. LCMS and ¹H NMR areconsistent withN-(1-(2,6-dichloro-7-fluoroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(226.3 mg, 0.623 mmol, 25.02% yield)¹H NMR indicates a singlediastereomer. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 8.52 (s, 1H), 8.47 (d,J=7.92 Hz, 1H), 8.01 (d, J=10.26 Hz, 1H), 5.66 (d, J=6.16 Hz, 1H), 4.83(q, J=6.60 Hz, 1H), 1.60 (d, J=6.74 Hz, 3H), 1.13 (s, 9H). LCMS (Method1): m/z 363 [M+H]⁺.

Step-5: 3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-onehydrochloride (II-3)

A sample ofN-(1-(2,6-dichloro-7-fluoroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(226.3 mg, 0.623 mmol) was mixed with 1,4-dioxane (3.5 mL) and 3.6% HCl(aqueous, 3.5 mL) and stirred at 95° C. overnight; the material quicklywent into solution upon heating. Once LCMS showed the reaction had goneto completion, the solution was evaporated under reduced pressure. Theresidue was dissolved in MeOH (˜10 mL), treated with heptane (˜15 mL),and evaporated again under reduced pressure. The resulting residue wasthen triturated with Et₂O, collected on a Hirsch funnel, and washed withEt₂O (20 mL) to provide 179.8 mg of the title compound as a yellowsolid. LCMS and ¹H NMR are consistent with3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one hydrochloride(179.8 mg, 0.649 mmol, 104% yield)¹H NMR (300 MHz, Methanol-d₄): δ ppm8.02 (s, 1H), 7.92 (d, J=7.62 Hz, 1H), 7.23 (d, J=9.97 Hz, 1H), 4.53 (q,J=6.84 Hz, 1H), 1.68 (d, J=6.74 Hz, 3H). LCMS (Method 1): m/z 241[M+H]⁺.

Example 6—Intermediate II-4:(S)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one (II-4)

Step-1: 2-Amino-5-chloro-4-fluorobenzoic acid

2-Amino-4-fluorobenzoic acid (50 g, 322.6 mmol) was dissolved in 700 mLof DMF and N-chlorosuccinimide (41 g, 305.5 mmol) was added portionwise. The reaction mixture was heated at 50° C. for 5 h. The mixture wascooled to room temperature, poured on to ice cold water to get thesolid. The solid was filtered and dissolved in EtOAc, then sat. NaCl(300 mL) was added. The aqueous layer was extracted with EtOAc (3×200mL). The combined organic phase was dried (Na₂SO₄) and evaporated to abrown solid (42 g, 69%) as desired product2-amino-5-chloro-4-fluorobenzoic acid.

Step-2: (2-Amino-5-chloro-4-fluorophenyl)methanol

2-Amino-5-chloro-4-fluorobenzoic acid (42 g, 221 mmol) was dissolved in100 mL of THF and BH₃.THF (712 mL of 1 M solution in THF, 712 mmol) wasadded dropwise over the period of 1 h at room temperature. The reactionmixture was heated at 50° C. overnight (18 h). The mixture was cooled toroom temperature, poured onto ice cold water, and sat. NaCl solution wasadded. The aqueous was extracted with EtOAc (3×200 mL). The combinedorganic phase was dried (Na₂SO₄), evaporated and purified by flashchromatography using 0-100% hexanes/ethyl acetate as eluent to affordthe desired product as a brown solid (17 g, 45%).

Step-3: 2-Amino-5-chloro-4-fluorobenzaldehyde

To a solution of (2-amino-5-chloro-4-fluorophenyl)methanol (22 g, 125.7mmol) in 1000 mL of chloroform was added MnO₂ (109 g, 1250 mmol) and thereaction mixture was stirred overnight at ambient temperature. Thereaction mixture was filtered, washed with EtOAc and evaporated. Theresulting crude product was passed through a pad of silica gel elutingwith 0 to 20% hexanes/EtOAc to give the pure product as a brown solid(19 g, 87%).

Step-4: 3-acetyl-6-chloro-7-fluoroquinolin-2(1H)-one

A mixture of 2-Amino-5-chloro-4-fluorobenzaldehyde (14 g, 173.6 mmol)and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (16 mL, 121 mmol) in m-xylene(500 mL) was refluxed for 1.5 h. The reaction mixture was cooled to roomtemperature and filtered. The collected solid was washed with m-xyleneand dried to yield the desired product (9.6 g, 50%) as off-white solid.

Step-5:(S)—N—((S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a mixture of 3-acetyl-6-chloro-7-fluoroquinolin-2(1H)-one (6.4 g,26.7 mmol) and (S)-2-methylpropane-2-sulfinamide (4.85 g, 40.06 mmol) inTHF (450 mL) was added Ti(OEt)₄ (14 mL, 66.7 mmol). The resultantmixture was stirred at 80° C. overnight. Upon the completion of thereaction, the reaction mixture was cooled to −60° C. and NaBH₄ (5.1 g,134 mmol) was added portion wise and then allowed to warm to roomtemperature overnight. The excess NaBH₄ was quenched with MeOH (20 mL),then with water (20 mL) and EtOAc (300 mL). The solution was filteredthrough a pad of celite. The filtrate was taken into a separatory funneland the organic layer was separated, dried (Na₂SO₄), concentrated andpurified by flash chromatography (SiO₂: hexanes/^(i)PrOH 0 to 20%) togive the title compound (4.5 g, 49%) as a yellow solid.

Step-6: (S)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one. HCl,(II-4)

To a mixture of(S)—N—((S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (3.5 g, 10.1 mmol) in MeOH (80 mL) was added 3Nmethanolic HCl (80 mL, 121 mmol). The resultant mixture was stirred atroom temperature overnight. To this mixture was added diethyl ether (60mL) and the resulting solid was filtered and dried to give the desiredproduct II-4 (2.1 g, 75%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆):δ 12.40 (br s, 1H), 8.24 (br s, 2H), 8.07-8.05 (m, 2H), 7.32 (d, J=10.4Hz, 1H), 4.5-4.15 (m, 1H), 1.53 (d, J=6.8 Hz, 3H). LCMS (Method 3): Rt3.47 min, m/z 241.1 [M+H]⁺.

Example 7—Intermediate II-5:(R)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one

Step-1: 6-chloro-7-fluoro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde

2,6-dichloro-7-fluoroquinoline-3-carbaldehyde (2.56 g, 10.49 mmol) washeated at reflux in concentrated HCl (12M, 100 mL) overnight, duringwhich the material did not appear to go into solution. The mixture wasallowed to cool, then was poured into water (750 mL). The slurry wasfiltered on a Buchner funnel, washed with water (750 mL), and dried toprovide impure6-chloro-7-fluoro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (2.1991 g,9.75 mmol, 93% yield) as a reddish brown solid. The material wassuitable for use as is. ¹H NMR (300 MHz, DMSO-d6): δ ppm 12.41 (s, 1H),10.20 (s, 1H), 8.49 (s, 1H), 8.28 (d, J=7.92 Hz, 1H), 7.25 (d, J=10.26Hz, 1H). LCMS: m/z+226 [M+H]⁺.

Step-2:(R,E)-N-((6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of 6-chloro-7-fluoro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde(2.20 g, 9.75 mmol) and (R)-2-methylpropane-2-sulfinamide (1.42 g, 11.72mmol) was placed in a 50 mL round bottom flask under an atmosphere ofnitrogen. THF (20 mL) and titanium (IV) isopropoxide (Ti(O^(i)Pr)₄) (5.8mL, 19.79 mmol) were added by syringe and the resulting suspension wasstirred at room temperature for one day, during which the mixture turneddark. The reaction mixture was quenched by dropwise addition ofsaturated aqueous NH₄Cl, resulting in precipitation. The mixture wastriturated with EtOAc (400 mL) and filtered on a Buchner funnel. Thefilter cake was then sonicated in 300 mL EtOAc for 15 minutes. Themixture was filtered on a Buchner funnel, and the filtrates from the twofiltrations were combined. The combined filtrate solution was washedwith brine (200 mL), dried (Na₂SO₄), filtered, and evaporated underreduced pressure to provide(R,E)-N-((6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide (3.22 g, 9.79 mmol, 100% yield) as an orangesolid. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.40 (br s, 1H), 8.75 (br s,1H), 8.65 (s, 1H), 8.27 (d, J=8.21 Hz, 1H), 7.25 (d, J=10.26 Hz, 1H),1.20 (s, 9H). LCMS: m/z 329 [M+H]⁺.

Step-3:(R)—N—((R)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

(R,E)-N-((6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(3.22 g, 9.79 mmol) was placed in a 500 mL round-bottom flask under anatmosphere of nitrogen. DCM (100 mL) was added and the resultingsuspension was cooled on a dry ice/chloroform bath (to approximately−60° C.). Methyl magnesium bromide (MeMgBr) (3M in ether, 10 mL, 30.0mmol) was added dropwise. The reaction mixture was stirred at −60° C.for several hours, and then allowed to warm to room temperatureovernight, resulting in a red solution. The solution was then cooled onan ice bath, treated dropwise with water (40 mL) and concentrated underreduced pressure. The resulting slurry was diluted with water (300 mL)and washed with EtOAc. The resulting emulsion was allowed to separateovernight. The layers were separated, and silica gel was added to theorganic layer. Most of the solvent was evaporated under reducedpressure. MeOH and heptane were added and the mixture was evaporatedunder reduced pressure to dryness. The material was purified by columnchromatography on a Biotage® MPLC chromatography system (using 50 gsilica gel column; eluted with 0 to 50% EtOAc in hexanes, with isocraticelution when peaks eluted) to provide(R)—N—((R)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(774.3 mg, 2.245 mmol, 23% yield) as a greenish solid. ¹H NMR shows asingle diastereomer. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.03 (s, 1H),7.98 (d, J=7.92 Hz, 1H), 7.89 (s, 1H), 7.22 (d, J=10.26 Hz, 1H), 5.67(d, J=7.92 Hz, 1H), 4.41-4.55 (m, 1H), 1.37 (d, J=6.74 Hz, 3H), 1.12 (s,9H). LCMS: m/z 345 [M+H]⁺.

Step 4: (R)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-onehydrochloride (II-5)

A solution of(R)—N—((R)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(773 mg, 2.242 mmol) in MeOH (20 mL) was cooled on an ice bath andtreated dropwise with 4M HCl in dioxane (12 mL), during which thematerial went into solution. The reaction was stirred 25 minutes, duringwhich time precipitate formed. The solvents were evaporated underreduced pressure at room temperature. The residue was triturated withethyl ether (50 mL), then the solid was collected on a Hirsch funnel andwashed with more ethyl ether (50 mL) to provide(R)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-one hydrochloride(613.5 mg, 2.214 mmol, 99% yield) as a yellow solid. ¹H NMR (300 MHz,Methanol-d₄): δ ppm 7.99 (s, 1H), 7.90 (d, J=7.62 Hz, 1H), 7.22 (d,J=9.67 Hz, 1H), 4.51 (q, J=6.64 Hz, 1H), 1.66 (d, J=7.04 Hz, 3H). LCMS:m/z 241 [M+H]⁺.

Example 8—Intermediate II-6:3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one

Step 1: 2,6-dichloro-7-methoxyquinoline-3-carbaldehyde

A tube was capped with a septum and placed under an atmosphere ofnitrogen. DMF (6.4 mL, 83 mmol) was added by syringe and then cooled onan ice bath. POCl₃ (25 mL, 268 mmol) was added dropwise by syringe (over20 minutes). The red solution was allowed to warm to room temperature(over 20 minutes), then the septum was removed, and the mixture wastreated with N-(4-chloro-3-methoxyphenyl)acetamide (5 g, 25.05 mmol) Thetube was sealed and the solution was stirred at 80° C. overnight. Thesolution was then pipetted onto ice, resulting in formation of a yellowprecipitate. The precipitate was collected on a Buchner funnel, washedwith water (1200 mL), and dried to provide 5.06 g of the title compoundas a pale yellow solid. LCMS and ¹H NMR are consistent with2,6-dichloro-7-methoxyquinoline-3-carbaldehyde (5.06 g, 19.76 mmol, 79%yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm 10.33 (s, 1H), 8.87 (s, 1H), 8.47(s, 1H), 7.64 (s, 1H), 4.08 (s, 3H). LCMS (Method 1): m/z 256 [M+H]⁺.

Step-2: 6-chloro-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde

2,6-Dichloro-7-methoxyquinoline-3-carbaldehyde (5.06 g, 19.76 mmol) washeated at reflux in concentrated HCl (12M, 185 mL) overnight. Thematerial went into solution during heating and then a solid precipitatedduring the course of the reaction. The mixture was allowed to cool andthen was poured into water (1500 mL) resulting in further precipitation.The slurry was filtered on a Buchner funnel, washed with water (1500mL), and dried to provide 4.04 g of the title compound as ayellowish-brown solid. LCMS and ¹H NMR are consistent with6-chloro-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (4.04 g,17.00 mmol, 86% yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.22 (s, 1H),10.16-10.18 (m, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 6.95 (s, 1H), 3.94 (s,3H). LCMS (Method 1): m/z 238 [M+H]⁺.

Step-3:N-((6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of6-chloro-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (2.00 g,8.42 mmol) and 2-methylpropane-2-sulfinamide (1.22 g, 10.07 mmol) wasplaced under an atmosphere of nitrogen. THF (20 mL) and titanium (IV)isopropoxide (Ti(O^(i)Pr)₄) (5.0 mL, 17.06 mmol) were added by syringeand the resulting suspension was stirred at room temperature overnight.Once LCMS indicated the reaction had gone to completion, the reactionwas quenched by dropwise addition of aqueous saturated NH₄Cl (10 mL).The mixture was triturated with EtOAc (450 mL), then filtered throughCelite® 545, and the Celite® was washed further with EtOAc (200 mL). Thefilter cake was then sonicated in EtOAc (450 mL) for 15 minutes, thenfiltered on a Buchner funnel. The two filtrates were combined, washedwith brine (200 mL), dried (Na₂SO₄), filtered, and evaporated underreduced pressure to provide 1.01 g of the title compound as a yellowsolid. LCMS and ¹H NMR are consistent with(E)-N-((6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(1.01 g, 2.96 mmol, 35.2% yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.21(s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.08 (s, 1H), 6.97 (s, 1H), 3.94(s, 3H), 1.19 (s, 9H). LCMS (Method 1): m/z 341 [M+H]⁺.

Step-4:N-(1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

N-((6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(265 mg, 0.778 mmol) was placed in a 50 mL round-bottom flask under anatmosphere of nitrogen. DCM (7 mL) was added, and the suspension wascooled on a dry ice/chloroform bath (to approx. −60° C.).Methylmagnesium bromide (MeMgBr) (3M in ether, 0.80 mL, 2.40 mmol) wasadded dropwise. The reaction mixture was stirred at −60° C. for severalhours, then allowed to warm to room temperature overnight, resulting inan orange solution. Once LCMS indicated the reaction had gone tocompletion, the suspension was cooled on an ice bath and treateddropwise with water (3 mL). The resulting mixture was diluted with water(75 mL) and extracted with EtOAc (75 mL+20 mL). Silica gel was added andthe EtOAc was evaporated under reduced pressure to provide a wetglobular mass. Heptane and MeOH were added and the mixture wasevaporated under reduced pressure to provide a powder. The material waspurified by column chromatography on a Biotage® MPLC chromatographysystem (eluted with 0 to 4.2% MeOH in DCM, with isocratic elution whenpeaks eluted). The product fractions provided 152.7 mg of the titlecompound as a blue-green brittle foam. LCMS and ¹H NMR are consistentwithN-(1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(152.7 mg, 0.428 mmol, 55% yield). LCMS (Method 1): m/z 357 [M+H]⁺.

Step-5: 3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-onehydrochloride (II-6)

A solution ofN-(1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (149.6 mg, 0.419 mmol) in MeOH (3.8 mL) was cooledon an ice bath and treated dropwise with 4M HCl in 1,4-dioxane (2.2 mL).The reaction was stirred for 25 minutes, during which time a smallamount of precipitate formed. The solvents were evaporated under reducedpressure at room temperature. The residue was triturated with 10 mL ofethyl ether, then collected on a Hirsch funnel, and washed with moreethyl ether to provide 115.6 mg of the title compound as a pale greensolid. LCMS and ¹H NMR are consistent with3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one hydrochloride(115.6 mg, 0.400 mmol, 95% yield)¹H NMR (300 MHz, Methanol-d₄): δ ppm7.95 (s, 1H), 7.77 (s, 1H), 6.97 (s, 1H), 4.51 (q, J=6.84 Hz, 1H), 3.98(s, 3H), 1.68 (d, J=7.04 Hz, 3H). LCMS (Method 1): m/z 253 [M+H]⁺.

Example 9—Intermediate II-7:(S)-3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one

Step-1: N-(4-chloro-3-methoxyphenyl)acetamide

To a solution of 4-chloro-3-methoxyaniline (50 g, 317 mmol) and DIPEA(110 mL, 635 mmol) in CH₂Cl₂ (700 mL) was added acetic anhydride (36 mL,381 mmol) dropwise at 0° C. and the reaction mixture was stirred at roomtemperature for 3 h. The reaction then was quenched with water (250 mL)and the organic layer was separated. The aqueous layer was extractedwith CH₂Cl₂ (100 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated and purified by flash chromatography with CH₂Cl₂/MeOH togive N-(4-chloro-3-methoxy phenyl)acetamide (71 g, quantitative yield)as a white solid.

Step-2: 2,6-Dichloro-7-methoxyquinoline-3-carbaldehyde

To POCl₃ (450 g, 274 mL, 2.95 mol) in a 2 L flask was added anhydrousDMF (83.5 g, 89 mL, 14 mol) drop wise. The reaction mixture was warmedup to room temperature and stirred for 20 min. After thatN-(4-chloro-3-methoxyphenyl)acetamide (65 g, 327 mmol) was added portionwise at room temperature and the mixture was heated to 90° C. overnight.The reaction mixture was then cooled to room temperature and carefullyquenched into aqueous NaHCO₃ solution. The precipitation obtained wasfiltered, washed with water (100 mL×3) and then dried in vacuum oven togive 60 g of title compound (73%).

Step-3: 6-Chloro-2,7-dimethoxyquinoline-3-carbaldehyde

To 2,6-dichloro-7-methoxyquinoline-3-carbaldehyde (40 g, 157 mmol) inMeOH (1 L) and THF (200 mL) was added NaOMe (16.9 g, 314 mmol) portionwise at room temperature. The reaction mixture was refluxed for 3 h.After cooling to room temperature, the reaction was quenched by additionof aqueous NH₄Cl solution (200 mL). The mixture was extracted with EtOAc(200 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated and purified by flash chromatography with hexanes/EtOAc(3:1) to give the desired product (37.89 g, 96%) as a yellow solid.

Step-4: 1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethanol

To a solution of 6-chloro-2,7-dimethoxyquinoline-3-carbaldehyde (36.74g, 151 mmol) in THF (1 L) at −78° C. was added a solution of MeMgCl inTHF (3 M, 75.5 mL, 226 mmol) drop wise. The reaction was stirred at roomtemperature for 3 h and then quenched with aqueous NH₄Cl solution (250mL). The organic layer was separated and the aqueous layer was extractedwith EtOAc (100 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated, and purified by silica gel chromatography withhexanes/EtOAc (3:1) to afford the title compound (38.06 g, 91%).

Step-5: 1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethanone

To 1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethanol (36.74 g, 137.6 mmol)in CH₂Cl₂ (1 L) at 0° C. was added DMP (70.0 g, 165.1 mmol) portionwise. The reaction was stirred at room temperature for 2 h, and then wasquenched with an aqueous solution of NaHCO₃ and Na₂S₂O₃. After stirringfor 15 min, both layers became clear. The organic layer was separatedand the aqueous layer was extracted with CH₂Cl₂ (100 mL×2). The combinedorganic layers were dried (Na₂SO₄), concentrated and purified by silicagel chromatography with hexanes/EtOAc (4:1) to afford the title compound(30.02 g, 80%) as a white solid.

Step-6:(R,E)-N-(1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide

To 1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethanone (30.07 g, 113.5 mmol)in THF/toluene (100 mL/1 L) at room temperature was added(R)-2-methylpropane-2-sulfinamide (27.5 g, 227 mmol,) and Ti(OiPr)₄ (97mL, 340.5 mmol,). The reaction was refluxed with a Dean-Stark apparatus.After the reaction was refluxed for 4 h and 300 mL of solvent wasremoved, the reaction was cooled to room temperature. The solvent wasremoved under vacuum, and 200 mL of EtOAc was added to the residue,followed by 100 mL of saturated aqueous NaHCO₃ solution. After stirringfor 10 min, the reaction mixture was passed through a pad of celite. Thefiltrate was extracted with EtOAc (200 mL×2), dried (Na₂SO₄),concentrated and purified by silica gel chromatography withhexanes/EtOAc (1:1) to give the title compound (34.28 g, 82%).

Step-7:(R)—N—((S)-1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To(R,E)-N-(1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide(34.28 g, 93.15 mmol) in THF (600 mL) at −78° C., was added 1 ML-selectride (121 mL, 121 mmol) in THF drop wise. The reaction mixturewas warmed to room temperature and stirred for 3 h. The reaction wasquenched with aqueous saturated NH₄Cl (300 mL) solution and thenextracted with EtOAc (200 mL×2). The combined organic layers were dried(Na₂SO₄), concentrated and purified by silica gel chromatography withhexanes/EtOAc (1:1) to afford the title compound (29.27 g, 85%).

Step-8: (S)-3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-onehydrochloride salt (II-7)

To(R)—N—((S)-1-(6-chloro-2,7-dimethoxyquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(30.35 g, 82 mmol) in dioxane (250 mL) was added 2 N HCl (250 mL) at rt.The reaction mixture was refluxed for 3 h, cooled to room temperatureand the solvent was removed under vacuum. The crude residue obtained wasdried under vacuum to give a crude product, which was further purifiedby trituration (CH₂Cl₂/MeOH/hexane) to obtain pure title compound II-7(17.65 g, 75%) as a white solid. ¹H NMR (300 MHz, DMSO-d6): δ 12.18 (s,1H), 8.24 (br, s, 3H), 7.99 (s, 1H), 7.86 (s, 1H), 7.02 (s, 1H), 4.41(m, 1H), 3.91 (s, 3H), 1.52 (d, J=6.87 Hz, 3H). LCMS (Method 3): Rt 3.48min, m/z 253.1 [M+H]⁺.

Example 10—Intermediate II-8:(R)-3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one

The title compound II-8 was prepared in the same procedure described forII-7, except using (S)-2-methylpropane-2-sulfinamide in Step-6(Scheme-3). ¹H NMR (300 MHz, Methanol-d₄): δ ppm 7.92 (s, 1H), 7.75 (s,1H), 6.95 (s, 1H), 4.48 (q, J=6.84 Hz, 1H), 3.96 (s, 3H), 1.65 (d,J=6.74 Hz, 3H). LCMS: m/z 253 [M+H]⁺.

Example 11—Intermediate II-9:3-(1-aminoethyl)-6-chloro-7-(pyridin-2-ylmethoxy) quinolin-2(1H)-one

Step-1: 4-chloro-3-(pyridin-2-ylmethoxy)aniline

A solution of 5-amino-2-chlorophenol (2.00 g, 13.93 mmolpyridin-2-ylmethanol (1.4 mL, 14.51 mmol), and triphenylphosphine (4.30g, 16.39 mmol) in THF (250 mL) was placed under an atmosphere ofnitrogen and treated with DEAD (2.6 mL, 16.42 mmol) The solution wasstirred at room temperature overnight. Once LCMS indicated the reactionhad gone to completion, the solution was treated with silica gel andevaporated under reduced pressure. The material was purified by columnchromatography on a Biotage® MPLC chromatography system (using a 340 gsilica gel column, eluted with 0 to 100% EtOAc in hexanes, then 2.3%MeOH in EtOAc) to provide the title compound as a light brown solid.LCMS and ¹H NMR are consistent with4-chloro-3-(pyridin-2-ylmethoxy)aniline (2.29 g, 9.76 mmol, 70.0% yield)with residual triphenylphosphine oxide. The crude was used in the nextstep without further purification. ¹H NMR (300 MHz, DMSO-d₆): δ ppm8.55-8.62 (m, 1H), 7.86 (ddd, J=7.77, 7.77, 1.76 Hz, 1H), 7.52 (d,J=7.92 Hz, 1H), 7.35 (dd, J=6.89, 5.42 Hz, 1H), 7.02 (d, J=8.50 Hz, 1H),6.37 (d, J=2.35 Hz, 1H), 6.15 (dd, J=8.50, 2.35 Hz, 1H), 5.28 (s, 2H),5.14 (s, 2H). LCMS (Method 1,): m/z 235 [M+H]⁺.

Step-2: N-(4-chloro-3-(pyridin-2-ylmethoxy)phenyl)acetamide

A solution of 4-chloro-3-(pyridin-2-ylmethoxy)aniline (5.22 g, 22.24mmol) and DIEA (4.30 mL, 24.62 mmol) in EtOAc (125 mL) was treated withAc₂O (2.30 mL, 24.38 mmol) The solution was stirred at room temperatureovernight, after which a thick white precipitate formed. EtOAc (300 mL)was added and the mixture was shaken until most of the precipitatedissolved. The organic layer was then washed with water and brine (125mL each), dried (Na₂SO₄) and filtered. Silica gel was added, and themixture was evaporated under reduced pressure. The residue was purifiedby column chromatography on a Biotage® MPLC chromatography system (usinga 100 g silica gel column, eluted with 0 to 5% MeOH in DCM) to provide3.23 g of the title compound as a white solid. LCMS and ¹H NMR areconsistent with N-(4-chloro-3-(pyridin-2-ylmethoxy)phenyl)acetamide(3.23 g, 11.67 mmol, 52.5% yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm 10.06(s, 1H), 8.56-8.62 (m, 1H), 7.87 (ddd, J=7.80, 7.80, 1.80 Hz, 1H), 7.53(d, J=7.62 Hz, 1H), 7.49 (d, J=2.05 Hz, 1H), 7.33-7.40 (m, 2H), 7.22(dd, J=8.65, 2.20 Hz, 1H), 5.21 (s, 2H), 2.02 (s, 3H). LCMS (Method 1):m/z 277 [M+H]⁺.

Step-3: 2,6-dichloro-7-(pyridin-2-ylmethoxy)quinoline-3-carbaldehyde

A tube was capped with a septum and placed under an atmosphere ofnitrogen. DMF (2.9 mL, 37.5 mmol) was added by syringe and then cooledon an ice bath. POCl₃ (11.4 mL, 122 mmol) was added dropwise by syringe(over 20 minutes). The solution was allowed to warm to room temperature(over 15 minutes) and the septum was removed. The mixture was treatedwith N-(4-chloro-3-(pyridin-2-ylmethoxy)phenyl)acetamide (3.16 g, 11.42mmol) The tube was again sealed and the solution was stirred at 80° C.overnight. The solution was then pipetted onto ice, resulting in theformation of a yellow precipitate. The precipitate was collected on aBuchner funnel, washed with water (500 mL), and dried to provide 2.88 gof the title compound as a pale yellow solid. LCMS and ¹H NMR areconsistent with2,6-dichloro-7-(pyridin-2-ylmethoxy)quinoline-3-carbaldehyde (2.88 g,8.64 mmol, 76% yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm 10.34 (s, 1H),8.89 (s, 1H), 8.66 (br d, J=4.10 Hz, 1H), 8.52 (s, 1H), 7.92-8.01 (m,1H), 7.75 (s, 1H), 7.69 (br d, J=7.62 Hz, 1H), 7.41-7.50 (m, 1H), 5.55(s, 2H). LCMS (Method 1): m/z 333 [M+H]⁺.

Step-4:6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinoline-3-carbaldehydeIV-3

A solution of2,6-dichloro-7-(pyridin-2-ylmethoxy)quinoline-3-carbaldehyde (2.88 g,8.64 mmol) in concentrated HCl (81 mL) was stirred at reflux (bathtemperature 100° C.) for one day, during which time the solution turnedorange. The solution was diluted with water (900 mL), resulting in theformation of a yellow precipitate. The precipitate was collected on aBuchner funnel, washed with water (750 mL), and dried under vacuum at60° C. to provide 2.27 g of the title compound as a yellow solid. LCMSand ¹H NMR are consistent with6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinoline-3-carbaldehydeIV-3 (2.27 g, 7.21 mmol, 83% yield) ¹H NMR (300 MHz, DMSO-d₆): δ ppm12.20 (s, 1H), 10.16-10.19 (m, 1H), 8.60-8.64 (m, 1H), 8.44 (s, 1H),8.14 (s, 1H), 7.90 (ddd, J=7.60, 7.60, 1.80 Hz, 1H), 7.57 (d, J=7.62 Hz,1H), 7.36-7.43 (m, 1H), 7.05 (s, 1H), 5.37 (s, 2H). LCMS (Method 1): m/z315 [M+H]⁺.

Step-5:(E)-N-((6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinoline-3-carbaldehyde(2.27 g, 7.21 mmol) and 2-methylpropane-2-sulfinamide (1.05 g, 8.66mmol) was placed in a 25 mL round bottom flask under an atmosphere ofnitrogen. THF (9 mL) and titanium (IV) isopropoxide (Ti(O^(i)Pr)₄) (4.3mL, 14.68 mmol) were added by syringe and the suspension was stirred atroom temperature for one day. Once LCMS indicated the reaction had goneto completion, the material was triturated with EtOAc (400 mL), thenfiltered through Celite® 545, and the filter cake was washed with EtOAc(100 mL). The filter cake was sonicated in EtOAc (400 mL) for fifteenminutes and then filtered on a Buchner funnel. The two filtrates werecombined and washed with brine (250 mL). The aqueous layer wasback-extracted with EtOAc (200 mL+100 mL). The three combined organiclayers were dried (Na₂SO₄), filtered, and evaporated under reducedpressure to provide 1.44 g of the title compound as a yellow solid. LCMSand ¹H NMR are consistent with(E)-N-((6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(1.44 g, 3.45 mmol, 47.8% yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.20(s, 1H), 8.74 (s, 1H), 8.62 (d, J=4.10 Hz, 1H), 8.60 (s, 1H), 8.13 (s,1H), 7.90 (ddd, J=7.80, 7.80, 1.80 Hz, 1H), 7.58 (d, J=7.92 Hz, 1H),7.40 (dd, J=7.18, 4.54 Hz, 1H), 7.06 (s, 1H), 5.36 (s, 2H), 1.19 (s,9H). LCMS (Method 1): m/z 418 [M+H]⁺.

Step-6:N-(1-(6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

(E)-N-((6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide (1.44 g, 3.45 mmol) was placed in a 250 mLround-bottom flask under an atmosphere of nitrogen. DCM (27 mL) wasadded and the suspension was cooled on a dry ice/chloroform bath (toapprox. −60° C.). Methylmagnesium bromide (MeMgBr) (3M in ether, 3.50mL, 10.50 mmol) was added dropwise. The cold bath was allowed to warm toroom temperature overnight resulting in an orange suspension. Once LCMSindicated the reaction had gone to completion, the suspension was cooledon an ice bath and treated dropwise with water (10 mL) resulting inemulsification. The emulsion was diluted with EtOAc (400 mL) and washedwith water (400 mL). Silica gel was added to the organic layer and thesolvent was evaporated under reduced pressure. The material was purifiedby column chromatography on a Biotage® MPLC chromatography system(eluted with 0 to 6% MeOH in DCM with isocratic elution when peakseluted) to provide 1.17 g of the title compound as a yellow brittlefoam. LCMS and ¹H NMR are consistent withN-(1-(6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(1.17 g, 2.70 mmol, 78% yield). NMR indicated a mixture ofdiastereomers. LCMS (Method 1): m/z 434 [M+H]⁺.

Step-7:3-(1-aminoethyl)-6-chloro-7-(pyridin-2-ylmethoxy)quinolin-2(1H)-onehydrochloride (II-9)

A solution ofN-(1-(6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(167.3 mg, 0.386 mmol) in MeOH (3.5 mL) was cooled on an ice bath andtreated dropwise with 4M HCl in 1,4-dioxane (2 mL). The reaction wasstirred for 20 minutes and within five minutes a precipitate began toform. The solvents were evaporated under reduced pressure at roomtemperature. The residue was triturated with 10 mL of ethyl ether,collected on a Hirsch funnel and washed with more ethyl ether to provide145.8 mg of the title compound as a pale yellow solid. LCMS and ¹H NMRare consistent with3-(1-aminoethyl)-6-chloro-7-(pyridin-2-ylmethoxy)quinolin-2(1H)-onehydrochloride (145.8 mg, 0.398 mmol, 103% yield)¹H NMR (300 MHz,Methanol-d₄): δ ppm 8.91-8.95 (m, 1H), 8.68 (ddd, J=7.90, 7.90, 1.50 Hz,1H), 8.29 (d, J=7.62 Hz, 1H), 8.04-8.11 (m, 1H), 8.00 (s, 1H), 7.90 (s,1H), 7.17 (s, 1H), 5.66 (s, 2H), 4.53 (q, J=6.84 Hz, 1H), 1.69 (d,J=6.74 Hz, 3H). LCMS (Method 1): m/z 352 [M+Na]⁺.

Example 12—Intermediate II-10:(S)-3-(1-aminoethyl)-6-chloro-7-(pyridin-2-ylmethoxy) quinolin-2(1H)-one

Step-1:1-(2,6-Dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethanone

To a solution of2,6-dichloro-7-(pyridin-2-ylmethoxy)quinoline-3-carbaldehyde (1.0 g, 3.0mmol) (prepared in the same procedure described for step-1-3 shown inScheme-4) in CH₂Cl₂ (40 mL) was added dropwise methyl magnesium bromide(MeMgBr) (3 M solution in diethyl ether, 1.5 mL, 4.50 mmol) at 0° C. Theresulting mixture was then stirred at ambient temperature for 1.5 hours.Upon completion of reaction, the mixture was slowly quenched with water(3 mL) and extracted with CH₂Cl₂ (50 mL). The organic layer wasseparated and dried over anhydrous Na₂SO₄. The solvents were evaporatedto dryness. The resulting residue was dissolved in CH₂Cl₂ (25 mL) andtreated with Dess-Martin Periodinate (2.54 g, 6.00 mmol). The mixturewas stirred at ambient temperature overnight. The mixture was thenquenched with an aqueous co-solution of 20% NaHCO₃ and 20% Na₂S₂O₃ (10mL) and stirred for 5 minutes at room temperature. The solution wasextracted with CH₂Cl₂ (40 mL), dried over anhydrous Na₂SO₄, filtered andevaporated. The resulting residue was purified by column chromatographyon an ISCO® chromatography system (SiO₂ column: eluted with CH₂Cl₂/MeOH0 to 10%) to afford the title compound (800 mg, 79%).

Step-2:(R,E)-N-(1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide

To a mixture of1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethanone (2.18 g,6.56 mmol) and (R)-2-methylpropane-2-sulfinamide (1.19 g, 9.84 mmol) inTHF:Toluene (40 mL:180 mL), was added titanium (IV) isopropoxide(Ti(O^(i)Pr)₄) (3.96 mL, 13.30 mmol). The resulting mixture was refluxedwith a Dean-Stark apparatus for 7 hours. The mixture was then cooled toroom temperature, quenched with water, and diluted with EtOAc (300 mL).The organic layer was washed with water (100 mL), dried over anhydrousNa₂SO₄, filtered and evaporated to dryness. The resulting residue waspurified by column chromatography on an ISCO® chromatography system(SiO₂ column: eluted with Hex/EtOAc 0 to 100%) to afford the titlecompound as yellow solid (1.4 g, 50% yield). The starting materialketone was also recovered (250 mg, 11% yield).

Step-3:(R)—N—((S)-1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of(R,E)-N-(1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 1.99 mmol) in THF (25 mL) at −40 to −50°C. was added L-selectride (1M in THF, 1.98 mL, 2.59 mmol) dropwise. Theresulting mixture was stirred at −40 to −50° C. for 2 hours. Uponcompletion of reaction, the mixture was quenched with ice at −50° C.,extracted with EtOAc (100 mL), dried, and evaporated. The resultingresidue was purified by column chromatography on an ISCO® chromatographysystem (SiO₂ column: Hex/EtOAc 0 to 100%) followed by trituration withhexanes-methylene chloride to afford the title compound (266 mg, 30%yield).

Step-4:(S)-3-(1-Aminoethyl)-6-chloro-7-(pyridin-2-ylmethoxy)quinolin-2(1H)-oneTFA salt (II-10)

To a mixture of(R)—N—((S)-1-(2,6-dichloro-7-(pyridin-2-ylmethoxy)quinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(1.1 g, 2.43 mmol) in 1,4-dioxane (6.6 mL), was added aqueous 1N HCl(6.6 mL) at room temperature. The resulting mixture was heated to 120°C. overnight. After TLC and MS showed completion of reaction, thesolvents were removed on a rotary evaporator and lyophilized to provideyellow solid. The crude solid was purified by reverse phasechromatography on an ISCO® chromatography system (C18 column: elutedwith H₂O/MoCN/0.1% CF CO₂H 0 to 100%) and the fractions were monitoredby LCMS. The pure fractions were combined and lyophilized to afford thetitle compound II-10 (920 mg, 86% yield) as the TFA salt. ¹H NMR (300MHz, DMSO-d₆): δ 12.17 (br s, 1H), 8.62 (d, J=4.95 Hz, 1H), 8.09 (br s,2H), 7.96-7.85 (m, 3H), 7.59 (d, J=7.9 Hz, 1H), 7.42-7.37 (m, 1H), 7.08(d, J=2.5 Hz, 1H), 5.33 (s, 2H), 4.39-4.38 (m, 1H), 1.51 (d, J=6.8 Hz,3H). LCMS (method 3): Rt 3.3 min, m/z 329.1 [M+H]⁺.

Example 13—Intermediate II-11:(S)-3-(1-aminoethyl)-6-chloro-1,8-naphthyridin-2(1H)-one

Step-1: 3-acetyl-6-chloro-1,8-naphthyridin-2(1H)-one

A mixture of 2-amino-5-chloronicotinaldehyde (1 g, 6.39 mmol) and2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.362 g, 9.58 mmol) in xylenes (10mL) was heated to reflux for 3 hours, then cooled to room temperature,filtered, and washed with xylenes twice to afford 914 mg of3-acetyl-6-chloro-1,8-naphthyridin-2(1H)-one (64.3% yield). ¹H NMR (300MHz, DMSO-d₆): δ 12.68 (br, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 8.39 (s,1H), 2.48 (s, 3H). LCMS (Method 1): Rt 1.60 min, m/z 223.03[M+H]⁺.

Step-2:(S)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of tetraethoxytitanium (512 mg, 2.25 mmol),(R)-2-methylpropane-2-sulfinamide (163 mg, 1.35 mmol) and3-acetyl-6-chloro-1,8-naphthyridin-2(1H)-one (200 mg, 0.898 mmol) in THF(15 mL) was heated to 80° C. overnight, then cooled to room temperature.To this mixture was added NaBH₄ (170 mg, 4.49 mmol) and the mixture wasslowly warmed up to room temperature overnight. MeOH was then added toquench any excess NaBH₄, followed by the addition of water. The mixturewas filtered to remove solids, then extracted with EtOAc twice, driedover Na₂SO₄, and concentrated. The residue was purified on a Biotage®chromatography system using a 25 g SiO₂ column eluted on a gradient(first 20% to 100% EtOAc/Hexanes, then 0-5% MeOH/DCM) to afford(S)—N—((S)-1-(2,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(123 mg, 42% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.40 (s, 1H), 7.74 (s,1H), 7.75 (s, 1H), 7.24 (s, 1H), 5.24 (d, J=9.45 Hz, 1H), 4.42 (m, 3H),1.54 (d, J=6.93 Hz, 3H), 1.20 (s, 9H). LCMS (Method 1): Rt 2.07 min, m/z328.98 [M+H]⁺.

Step-3: (S)-3-(1-aminoethyl)-6-chloro-1,8-naphthyridin-2(1H)-one (II-11)

To a solution of((S)—N—((S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(123 mg, 0.375 mmol) in MeOH (5 mL) was added HCl (2 mL, 8.00 mmol, 4Min 1,4-dioxane). The mixture was then stirred at room temperatureovernight. To this mixture was added 6 mL of ethyl ether and theresulting precipitate was filtered, washed with ethyl ether (2×), driedand concentrated to afford(S)-3-(1-aninoethyl)-6-chloro-1,8-naphthyridin-2(1H)-one, HCl (96 mg.98% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 12.75 (br s, 1H), 8.60-8.35 (s,1H), 8.26 (br, 1H) 8.07 (s, 1H), 4.40-4.50 (m, 1H), 1.51 (d, J=6.78 Hz,3H). LCMS (Method 1): Rt 0.87 min, m/z 224.99 [M+H]⁺.

Example 14—Intermediate II-12:(R)-3-(1-aminoethyl)-6-chloroquinoxalin-2(1H)-one

Step-1: Ethyl 3-((4-chloro-2-nitrophenyl)amino)-3-oxopropanoate

To a solution of 4-chloro-2-nitroaniline (42.3 g, 245 mmol) in CH₂Cl₂ (1L) was added ethyl 3-chloro-3-oxopropanoate (48 g, 319 mmol) dropwiseand the reaction mixture was stirred at room temperature overnight. Thesolvent was removed under vacuum and the resulting residue was dissolvedin a minimum amount of MTBE (200 mL) and hexanes (800 mL) which wasslowly added. Any product that precipitated out from solution wasfiltered and the filtrate was concentrated and purified by columnchromatography ISCO® chromatography system with hexanes/ethyl acetategradient elution to afford additional desired product. The titlecompound was obtained in 98% yield (69.85 g).

Step-2: 7-Chloro-2-(ethoxycarbonyl)-3-oxo-3,4-dihydroquinoxaline 1-oxide(A) and 7-Chloro-2-(methoxycarbonyl)-3-oxo-3,4-dihydroquinoxaline1-oxide (B)

To a solution of ethyl 3-((4-chloro-2-nitrophenyl)amino)-3-oxopropanoate(68 g, 238 mmol) and methyl benzoate (150 mL) in anhydrous DMF (500 mL)at 0° C. was added dropwise KO^(t)Bu (1M solution in THF, 500 mL, 500mmol). The reaction mixture was stirred at 0° C. for 4 hours and thenquenched with saturated NH₄Cl aqueous solution. The mixture wasextracted with CH₂Cl₂ (300 mL×3). The combined organic layers were dried(Na₂SO₄), concentrated, and purified by SiO₂ flash chromatography andeluted with CH₂Cl₂/MeOH to afford a mixture of A/B (42.54 g, 67% yield,A/B ratio 1:2) as a solid. This was used in the next step withoutfurther purification.

Step 3: Ethyl 7-chloro-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (D)and methyl 7-chloro-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (C)

To a mixture of compounds A and B (42.54 g, 159 mmol) in DMF (200 mL)was added PBr₃ (85.9 g, 318 mmol) dropwise at room temperature. Thereaction mixture was stirred at room temperature for 3 hours and wasthen quenched with ice water and extracted with CH₂Cl₂ (200 mL×3). Thecombined organic layers were dried (Na₂SO₄), concentrated, and purifiedby flash chromatography using CH₂Cl₂/MeOH (9:1) as eluent to afford C/D(36.6 g, 91% yield) as a solid. This was used in the next step withoutfurther purification.

Step-4: Ethyl 3,7-dichloroquinoxaline-2-carboxylate (E) and methyl3,7-dichloro quinoxaline-2-carboxylate (F)

To a mixture of compounds C/D (36.6 g, 145 mmol) in a 1 L flask wasadded POCl₃ (150 mL) in one portion and the resulting mixture wasrefluxed for 3 hours. The mixture was then cooled to room temperatureand carefully quenched with aqueous NaHCO₃ solution. The mixture wasextracted with CH₂Cl₂ (200 mL×3). The combined organic layer was dried(Na₂SO₄), concentrated, and purified by SiO₂ flash chromatography usinghexane/ethyl acetate (9:1) as eluent to afford E/F (23.7 g, 61% yield)as a solid. This mixture was used in the next step without furtherpurification.

Step-5: Methyl 7-chloro-3-methoxyquinoxaline-2-carboxylate

To a mixture of compounds E/F (22.11 g, 81.9 mmol) in THF/MeOH (9:1, 300mL) was added NaOMe (0.5 M, 360 mL) dropwise at 0° C. The resultingmixture was stirred at room temperature for 3 hours and quenched withsolid NH₄Cl (20 g). The solvent was removed under vacuum and water wasadded (200 mL). The mixture was extracted with CH₂Cl₂ (150 mL×3) and thecombined organic layers were dried (Na₂SO₄), concentrated, and purifiedby SiO₂ flash chromatography using hexanes/ethyl acetate (9:1) as eluentto afford the title compound (19.1 g, 88% yield) as a solid.

Step-6: 7-Chloro-3-methoxyquinoxaline-2-carbaldehyde (G) andoxybis((7-chloro-3-methoxyquinoxalin-2-yl)methanol) (H)

To methyl 7-chloro-3-methoxyquinoxaline-2-carboxylate (5.3 g, 20 mmol)in CH₂Cl₂ (250 mL) was added diisobutylaluminum hydride (1 M, 30 mL)dropwise at −78° C. The resulting mixture was stirred at −78° C. for 3hours and was then quenched with MeOH (at −78° C., 20 mL). Afterstirring for 0.5 hours, the mixture was warmed to room temperature andpotassium sodium L-tartrate aqueous solution (100 mL) was added. Theorganic layer was then separated, and the aqueous layer was extractedwith CH₂Cl₂ (50 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated, and purified by SiO₂ flash chromatography usinghexanes/ethyl acetate (1:1) as eluent to afford G (1.02 g, 23% yield)and H (2.24 g, 50% yield). The structure of H was assigned based on MSand ¹H NMR.

Step-7:(R,E)-N-((7-chloro-3-methoxyquinoxalin-2-yl)methylene)-2-methylpropane-2-sulfinamide

To compound H (2.24 g, 5.1 mmol) in DCE (300 mL) at room temperature wasadded (R)-2-methylpropane-2-sulfinamide (2.44 g, 20.1 mmol) and CuSO₄(4.85 g, 30.3 mmol). The reaction was heated to 60° C. and stirred for 4hours. The reaction mixture was then cooled to room temperature andquenched with 50 mL of saturated aqueous NaHCO₃ solution. After stirringfor 10 minutes, the reaction mixture was filtered through a pad ofCelite®. The filtrate was extracted with CH₂Cl₂ (50 mL×3), dried(Na₂SO₄), concentrated, and purified by column chromatography on anISCO® chromatography system using hexanes/ethyl acetate as eluent toafford the title compound (2.21 g, 67% yield).

Step-8:(R)—N—((R)-1-(7-chloro-3-methoxyquinoxalin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

To(R,E)-N-((7-chloro-3-methoxyquinoxalin-2-yl)methylene)-2-methylpropane-2-sulfinamide(2.21 g, 6.8 mmol) in CH₂Cl₂ (150 mL) was added methyl magnesiumchloride (MeMgCl) (3M in THF, 3.4 mL) dropwise at −78° C. The resultingmixture was stirred at −78° C. for 2 hours and was then quenched withaqueous NH₄Cl solution (20 mL). After stirring for 10 minutes, theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂ (25 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated, and purified by column chromatography on an ISCO®chromatography system using hexanes/ethyl acetate as eluent to affordthe title compound (1.18 g, 51% yield).

Step-9: (R)-3-(1-aminoethyl)-6-chloroquinoxalin-2(1H)-one (II-12)

To the compound(R)—N—((R)-1-(7-chloro-3-methoxyquinoxalin-2-yl)ethyl)-2-methylpropane-2-sulfinamide(1.29 g, 3.46 mmol) in CH₃CN (100 mL) was added iodotrimethylsilane(3.46 g, 17.3 mmol) dropwise at 0° C. The mixture was then refluxed for2 hours, cooled to room temperature, and quenched with MeOH (10 mL). Thesolvent was removed under vacuum, and the residue was purified byreverse C-18 chromatography on an ISCO® chromatography system usingwater (0.1% TFA)/CH₃CN (0.1% TFA) as eluent to afford the compound II-12(1.22 g, 95% yield) as a TFA salt.

Example 15—Intermediate II-13:(S)-3-(1-aminoethyl)-6-chloroquinoxalin-2(1H)-one

Step-1:(S,E)-N-((7-chloro-3-methoxyquinoxalin-2-yl)methylene)-2-methylpropane-2-sulfinamide

To compound H (2.31 g, 5.2 mmol) in DCE (300 mL) at room temperature wasadded (S)-2-methylpropane-2-sulfinamide (2.52 g, 20.8 mmol) and CuSO₄(5.0 g, 31.2 mmol). The resulting reaction mixture was heated to 60° C.and stirred for 4 hours. The reaction mixture was then cooled to roomtemperature and quenched with 50 mL of saturated aqueous NaHCO₃solution. After stirring for 10 minutes, the mixture was filteredthrough a pad of Celite®. The filtrate was extracted with CH₂Cl₂ (50mL×3), dried (Na₂SO₄), concentrated, and purified by columnchromatography on an ISCO® chromatography system using hexanes/ethylacetate as eluent to afford the title compound (2.62 g, 78% yield).

Step-2:(S)—N—((S)-1-(7-chloro-3-methoxyquinoxalin-2-yl)ethyl)-2-methylpropane-2-sulfinamide

To compound(S,E)-N-((7-chloro-3-methoxyquinoxalin-2-yl)methylene)-2-methylpropane-2-sulfinamide(2.62 g, 8.0 mmol) in CH₂Cl₂ (150 mL) was added methyl magnesiumchloride (MeMgCl) (3M in THF, 4.0 mL) dropwise at −78° C. The resultingmixture was stirred at −78° C. for 2 hours and was then quenched withaqueous NH₄Cl solution (20 mL). After stirring for 10 minutes, theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂ (25 mL×3). The combined organic layers were dried (Na₂SO₄),concentrated, and purified by column chromatography on an ISCO®chromatography system using hexanes/ethyl acetate as eluent to affordthe title compound (1.69 g, 62%).

Step-14: (S)-3-(1-aminoethyl)-6-chloroquinoxalin-2(1H)-one (II-13)

To the compound(S)—N—((S)-1-(7-chloro-3-methoxyquinoxalin-2-yl)ethyl)-2-methylpropane-2-sulfinamide(350 mg, 1.03 mmol) in CH₃CN (40 mL) was added iodotrimethylsilane (1.03g, 5.15 mmol) dropwise at 0° C. The mixture was then refluxed for 2hours. After it was cooled to room temperature, the reaction wasquenched with MeOH (2 mL). The solvent was removed under vacuum, and theresidue was purified by reverse C-18 chromatography on an ISCO®chromatography system using water (0.1% TFA)/CH₃CN (0.1% TFA) as eluentto afford the title compound (267 mg, 79% yield) as a TFA salt.

Example 16—Intermediate II-14:(3-((S)-1-aminoethyl)-6-chloro-7-((R)-1-(pyridin-2-yl)ethoxy)quinolin-2(1H)-one

Step-1: tert-butyl(3-((tert-butyldimethylsilyl)oxy)-4-chlorophenyl)carbamate

A solution of 5-amino-2-chlorophenol (10.00 g, 69.7 mmol) in THF (350mL) was treated with di-tert-butyl dicarbonate (20 mL, 86 mmol) andstirred at reflux overnight. The solvent was evaporated under reducedpressure to provide a brown oil. The oil was then dissolved in EtOAc(300 mL), washed with water, saturated aqueous NaHCO₃, and brine (300 mLeach), dried (Na₂SO₄), filtered, and evaporated under reduced pressureto provide 21.01 g of impure tert-butyl(4-chloro-3-hydroxyphenyl)carbamate as a brown oil (LCMS: m/z 244[M+H]⁺). This material was dissolved in DMF (130 mL) and cooled on anice bath. Imidazole (11.74 g, 172 mmol) was then added slowly (over ˜10minutes). A solution of TBDMS-Cl (14.98 g, 99 mmol) in DMF (45 mL) wasadded (over ˜2 minutes). The ice bath was removed and the solution wasstirred at room temperature overnight. Once LCMS indicated the reactionhad gone to completion, the solution was diluted with EtOAc (1 L) andwashed with water (2×600 mL), half-saturated aqueous NaHCO₃ (600 mL),half-saturated aqueous NH₄Cl (600 mL), saturated NaHCO₃ (600 mL), andbrine (600 mL). The organic layer was dried (MgSO₄), filtered, andevaporated under reduced pressure to provide 28.00 g of a brown solid.The sample was dissolved in EtOAc, silica gel (33 g) was added, and thesolvent was evaporated under reduced pressure. The material was dividedinto two batches, each of which was purified by column chromatography ona Biotage® MPLC chromatography system using a 330 g silica gel columneluted with 0 to 5% EtOAc in hexanes and with isocratic elution at 4.5%or 5% EtOAc when the product eluted. The product fractions werecollected and provided 21.76 g of tert-butyl(3-((tert-butyldimethylsilyl)oxy)-4-chlorophenyl)carbamate (21.76 g,60.8 mmol, 88% yield) as a peach-colored solid. ¹H NMR (300 MHz,DMSO-d₆): δ ppm 9.43 (s, 1H), 7.23-7.28 (m, 1H), 7.22 (d, J=2.35 Hz,1H), 7.09-7.16 (m, 1H), 1.46 (s, 9H), 0.99 (s, 9H), 0.21 (s, 6H). LCMS(Method 1): m/z 358 [M+H]⁺.

Step-2: tert-butyl (4-chloro-2-formyl-5-hydroxyphenyl)carbamate (J)

An oven-dried 3-necked 500 mL round bottom flask was charged withtert-butyl (3-((tert-butyldimethylsilyl)oxy)-4-chlorophenyl)carbamate(10 g, 27.9 mmol) An oven-dried addition funnel was attached, and thesystem was flushed with nitrogen. Ethyl ether (113 mL) was added bysyringe. The resulting yellow solution was cooled on an acetonitrile/dryice bath (to approximately −40° C.). t-BuLi (1.7 M in pentane, 40 mL,68.0 mmol) was then added to the addition funnel by cannula. The t-BuLisolution was added dropwise to the ether solution (over ˜10 minutes),during which time the ether solution gradually became cloudy with aprecipitate. The mixture was stirred at about −40° C. for 2.5 hours,then DMF (11 mL) was added dropwise by syringe (over −10 minutes),during which time the solids went back into solution. Theacetonitrile/dry ice bath was replaced with an ice bath, and the yellowsolution was stirred at 0° C. for 1.75 hours. The reaction was thenquenched by dropwise addition of water (25 mL), resulting in formationof an orange precipitate. The ice bath was removed and the sample wasdiluted with water (125 mL), resulting in dissolution of theprecipitate. The mixture was shaken, and the layers were separated. Theaqueous layer was acidified to pH ˜4-5 with AcOH. The resultingprecipitate was extracted with EtOAc (200 mL), washed with water (2×100mL), dried (Na₂SO₄), filtered, and evaporated under reduced pressure toprovide tert-butyl (4-chloro-2-formyl-5-hydroxyphenyl)carbamate as ayellow solid (4.79 g, 17.63 mmol, 63% yield). ¹H NMR (300 MHz, DMSO-d₆):δ ppm 11.72 (s, 1H), 10.50 (s, 1H), 9.68 (br s, 1H), 7.99 (s, 1H),7.88-7.91 (m, 1H), 1.48 (s, 9H). LCMS (Method 1): m/z 216 (M-56, loss oft-Bu).

Step-3: (R)-tert-butyl(4-chloro-2-formyl-5-(1-(pyridin-2-yl)ethoxy)phenyl)carbamate

A mixture of (S)-1-(pyridin-2-yl)ethanol (454.3 mg, 3.69 mmol)tert-butyl (4-chloro-2-formyl-5-hydroxyphenyl)carbamate (1 g, 3.68 mmol)and triphenylphosphine (1.158 g, 4.42 mmol) was placed in a 100 mL roundbottom flask under an atmosphere of nitrogen. THF (40 mL) was added bysyringe. The resulting yellow solution was cooled on an ice bath andthen DIAD (0.86 mL, 4.42 mmol) was added dropwise. The ice bath wasremoved and the solution was stirred at room temperature overnight. OnceLCMS indicated the reaction had gone to completion, silica gel was addedand the solvent was evaporated under reduced pressure. The sample waspurified by column chromatography on a Biotage® MPLC chromatographysystem (using a 50 g silica gel column eluted with 0 to 13% EtOAc inhexanes) to provide 473.7 mg of a white solid. LCMS and NMR areconsistent with (R)-tert-butyl(4-chloro-2-formyl-5-(1-(pyridin-2-yl)ethoxy)phenyl)carbamatecontaminated with phenolic starting material (˜5:1 product to startingmaterial by NMR). The material was used for next step without furtherpurification. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 10.42 (s, 1H), 9.73 (s,1H), 8.54-8.60 (m, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.82 (ddd, J=7.80,7.80, 1.80 Hz, 1H), 7.44 (br d, J=7.90 Hz, 1H), 7.30-7.36 (m, 1H), 5.64(q, J=6.35 Hz, 1H), 1.67 (d, J=6.45 Hz, 3H), 1.46 (s, 9H). LCMS (Method1): m/z 377 [M+H]⁺.

Step-4: (S)-ethyl 3-((tert-butoxycarbonyl)amino)butanoate (K)

A suspension of (S)-3-aminobutanoic acid (6.25 g, 60.6 mmol) in EtOH(27.5 mL) was cooled on an ice bath. Thionyl chloride (7.5 mL, 103 mmol)was then added dropwise over 40 minutes, during which time the aminoacid went into solution. The ice bath was allowed to melt, and thesolution was stirred at room temperature overnight. The mixture wasevaporated under reduced pressure, and the residue was mixed with moreEtOH (60 mL) and again evaporated under reduced pressure to provide anoil. The oil was dissolved in DCM (55 mL) and cooled on an ice bath. TEA(25 mL, 179 mmol) was added dropwise over 15 minutes with stirring,resulting in a milky mixture. Di-tert-butyl dicarbonate (17 mL, 73.2mmol) was then added. The ice bath was allowed to melt, and the mixturewas stirred at room temperature for five days. The resulting mixture wasfiltered through Celite® 545 on a Buchner funnel, and the filter cakewas washed with DCM (50 mL). The filtrate was washed with saturatedaqueous citric acid (20 mL) and water (2×100 mL), dried (MgSO₄),filtered, and evaporated under reduced pressure to provide the titlecompound as a clear oil. ¹H NMR is consistent with (S)-ethyl3-((tert-butoxycarbonyl)amino)butanoate (13.47 g, 58.2 mmol, 96% yield).¹H NMR (300 MHz, CDCl₃): δ ppm 4.95 (br s, 1H), 4.15 (q, J=7.13, 2H),3.98-4.10 (m, 1H), 2.40-2.57 (m, 2H), 1.44 (s, 9H), 1.27 (t, J=7.18,3H), 1.22 (d, J=6.74, Hz, 3H).

Step-5 & 6:3-((S)-1-aminoethyl)-6-chloro-7-((R)-1-(pyridin-2-yl)ethoxy)quinolin-2(1H)-onehydrochloride (II-14)

An oven-dried 25 mL round bottom flask and stir bar were placed under anatmosphere of nitrogen. THF (2.25 mL) and diisopropylamine (0.27 mL,1.894 mmol) were then added by syringe. The solution was cooled using adry ice/acetone bath (−78° C.) and n-BuLi (1.6 M in hexane, 1.15 mL,1.84 mmol) was added dropwise over 5 minutes. After stirring for 10minutes, a solution of (S)-ethyl 3-((tert-butoxycarbonyl)amino)butanoateK (115.3 mg, 0.499 mmol) in THF (0.5 mL) was added dropwise (over 5minutes). The solution was stirred for 75 minutes at −78° C. and then asolution of (R)-tert-butyl(4-chloro-2-formyl-5-(1-(pyridin-2-yl)ethoxy)phenyl)carbamate (188.7 mg,0.501 mmol) in THF (1.0 mL) was added dropwise by syringe. The reactionsolution became yellow when the aldehyde was added. The reaction wasstirred at −78° C. for 13 minutes and then quenched by the addition ofsaturated aqueous NH₄Cl solution (2.5 mL). The mixture was partitionedbetween EtOAc and water (10 mL each). The organic layer was dried(MgSO₄), filtered, and evaporated under reduced pressure to provide animpure mixture of isomers of (3S)-ethyl3-((tert-butoxycarbonyl)amino)-2-((2-((tert-butoxycarbonyl)amino)-5-chloro-4-((R)-1-(pyridin-2-yl)ethoxy)phenyl)(hydroxy)methyl)butanoate as a yellow oil (344.8 mg; LCMS: m/z+608 [M+H]⁺). The crudematerial (334 mg) was dissolved in 1,4-dioxane (5 mL) treated with 12Maqueous HCl (0.125 mL), and stirred at 110° C. for 90 minutes, duringwhich time a red material precipitated. The mixture was allowed to cooland the supernatant was decanted and discarded. Heptane (˜4 mL) wasadded to the red precipitate remaining in the round bottom and thenevaporated under reduced pressure to provide 161.8 mg of a red solid.The material was triturated with ^(i)PrOH (5 mL) and the resultingprecipitate was collected on a Hirsch funnel and washed with ^(i)PrOH (1mL) and ethyl ether (˜20 mL) to provide3-((S)-1-aminoethyl)-6-chloro-7-((R)-1-(pyridin-2-yl)ethoxy)quinolin-2(1H)-onehydrochloride (104.2 mg, 0.274 mmol, 55% yield) as a red solid, impurebut suitable for use as it is. ¹H NMR (300 MHz, Methanol-d₄): δ ppm8.81-8.87 (m, 1H), 8.55-8.64 (m, 1H), 8.18 (d, J=7.92 Hz, 1H), 7.96-8.04(m, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 6.99 (s, 1H), 5.98 (q, J=6.84 Hz,1H), 4.48 (q, J=6.84 Hz, 1H), 1.86 (d, J=6.45 Hz, 3H), 1.64 (d, J=6.74Hz, 3H). LCMS (Method 1): m/z 344 [M+H]⁺.

Example 17—Intermediate II-15:(S)-3-(1-aminoethyl)-6-chloro-7-(cyclopropylmethoxy) quinolin-2(1H)one

Step-1: tert-butyl(4-chloro-5-(cyclopropylmethoxy)-2-formylphenyl)carbamate

A mixture of cyclopropylmethanol (0.145 mL, 1.838 mmol) tert-butyl(4-chloro-2-formyl-5-hydroxyphenyl)carbamate J (499.4 mg, 1.838 mmol)and triphenylphosphine (579.4 mg, 2.209 mmol) was placed in a 100 mLround bottom flask under an atmosphere of nitrogen and THF (20 mL) wasthen added by syringe. The resulting orange solution was cooled on anice bath and DIAD (0.43 mL, 2.184 mmol) was added dropwise. The ice bathwas removed and the solution was stirred at room temperature for 48hours. Once LCMS indicated the reaction had gone to completion, silicagel was added and the solvent was evaporated under reduced pressure. Thesample was purified by column chromatography on a Biotage® MPLCchromatography system using a 25 g silica gel column eluted with 0 to 3%EtOAc in hexanes to provide tert-butyl(4-chloro-5-(cyclopropylmethoxy)-2-formylphenyl)carbamate (410.6 mg,1.260 mmol, 68.6% yield) as a yellowish solid. ¹H NMR (300 MHz,DMSO-d₆): δ ppm 10.57 (s, 1H), 9.75 (s, 1H), 7.95-8.00 (m, 2H), 4.02 (d,J=7.04 Hz, 2H), 1.49 (s, 9H), 1.23-1.31 (m, 1H), 0.57-0.66 (m, 2H),0.38-0.46 (m, 2H). LCMS (Method 1): m/z 270 (loss of t-Bu).

Step-2 & 3:(S)-3-(1-aminoethyl)-6-chloro-7-(cyclopropylmethoxy)quinolin-2(1H)-onehydrochloride (II-15)

An oven-dried 25 mL round bottom flask and stir bar were placed under anatmosphere of nitrogen and THF (5.6 mL) and diisopropylamine (0.53 mL,3.72 mmol) were added by syringe. The solution was cooled on a dryice/acetone bath (to −78° C.) and n-BuLi (1.6 M in hexane, 2.35 mL, 3.76mmol) was added dropwise over a 5 minute period. After stirring for 15minutes, a solution of (S)-ethyl 3-((tert-butoxycarbonyl)amino)butanoateK (286 mg, 1.238 mmol) THF (1.25 mL) was added dropwise (over 5minutes). The solution was stirred for 80 minutes at −78° C. and asolution of tert-butyl(4-chloro-5-(cyclopropylmethoxy)-2-formylphenyl)carbamate (403.2 mg,1.238 mmol) in THF (2.5 mL) was added dropwise by syringe. The reactionsolution became yellow when the aldehyde was added. The reaction wasstirred at −78° C. for 12 minutes and then quenched by addition ofsaturated aqueous NH₄Cl solution (6 mL). The mixture was partitionedbetween EtOAc and water (25 mL each) and the organic layer was dried(MgSO₄), filtered, and evaporated under reduced pressure to provide724.5 g of a yellowish oil. The material was dissolved in 1,4-dioxane(12.5 mL) treated with 12M HCl (aqueous; 0.32 mL), and stirred at 110°C. for 70 minutes during which time the solution became thick with apink precipitate. The sample was allowed to cool and the solvent wasevaporated under reduced pressure to provide 1.13 g of a fibrous redsolid. The material was triturated with i-PrOH (15 mL) and the resultingprecipitate was collected on a Buchner funnel and washed with i-PrOH (20mL) and ethyl ether (˜60 mL) to provide(S)-3-(1-aminoethyl)-6-chloro-7-(cyclopropylmethoxy)quinolin-2(1H)-onehydrochloride (146.1 mg, 0.444 mmol, 36% yield) as a papery white solid.¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.13 (br s, 1H), 8.21 (br s, 3H), 7.98(s, 1H), 7.86 (s, 1H), 6.98 (s, 1H), 4.32-4.46 (m, 1H), 3.96 (d, J=6.40Hz, 2H), 1.51 (d, J=6.70 Hz, 3H), 1.21-1.35 (m, 1H), 0.55-0.68 (m, 2H),0.35-0.46 (m, 2H). LCMS (Method 1): m/z 293 [M+H]⁺.

Example 18—Intermediate II-16:3-(1-Aminoethyl)-6-chloro-7-((3,3-difluorocyclobutyl)methoxy)quinolin-2(1H)-one

Step-1: N-(4-Chloro-3-((3,3-difluorocyclobutyl)methoxy)phenyl)acetamide

A solution of 5-amino-2-chlorophenol (3 g, 20.90 mmol)(3,3-difluorocyclobutyl)methanol (2.66 g, 21.78 mmol) in THF (375 mL)was placed under an atmosphere of nitrogen and treated with DEAD (3.90mL, 24.63 mmol). The solution was stirred at room temperature for 48hours. Once LCMS indicated adequate progression of the reaction, thesilica gel was added to the solution and evaporated under reducedpressure. The material was purified by column chromatography on aBiotage® MPLC chromatography system (using a 340 g silica gel columneluted with 0 to 100% EtOAc in hexanes with isocratic elution when peakseluted) to provide 3.89 g of the title compound as a brown liquid. LCMSwas consistent with impure4-chloro-3-((3,3-difluorocyclobutyl)methoxy)aniline (m/z 248 [M+H]⁺).The sample was dissolved in EtOAc (80 mL) and treated with DIEA (3.00mL, 17.18 mmol) and Ac₂O (1.60 mL, 16.96 mmol). The solution was stirredat room temperature overnight. The solution was then washed with waterand brine (50 mL each), dried (Na₂SO₄), filtered, and evaporated underreduced pressure. The residue was purified by column chromatography on aBiotage® MPLC chromatography system (using a 50 g silica gel column,eluted with 0 to 50% EtOAc in hexanes with isocratic elution when peakseluted) to provide 3.16 g of the title compound as a light brown oil,which slowly crystallized on standing. LCMS and ¹H NMR are consistentwith N-(4-chloro-3-((3,3-difluorocyclobutyl)methoxy)phenyl)acetamide(3.16 g, 10.91 mmol, 52% yield) In the NMR one proton is obscured by thesolvent signal. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 11.91 (s, 1H),8.54-8.67 (m, 1H), 7.80-7.95 (m, 2H), 7.68 (s, 1H), 7.56 (d, J=7.30 Hz,1H), 7.34-7.44 (m, 1H), 7.29 (d, J=9.10 Hz, 1H), 7.13-7.22 (m, 1H), 7.03(s, 1H), 6.31 (br s, 1H), 6.22 (d, J=7.90 Hz, 1H), 5.30 (s, 2H),4.10-4.26 (m, 2H), 3.78 (s, 3H). LCMS (Method 1): m/z 290 [M+H]⁺.

Step-2:2,6-Dichloro-7-((3,3-difluorocyclobutyl)methoxy)quinoline-3-carbaldehyde

A tube was capped with a septum and placed under an atmosphere ofnitrogen. DMF (2.15 mL, 27.8 mmol) was then added by syringe and theresulting reaction mixture was cooled on an ice bath. POCl₃ (8.40 mL, 90mmol) was added dropwise by syringe (10 minutes) during which time awhite material precipitated. The solution was then allowed to warm toroom temperature over 10 minutes and the mixture was treated withN-(4-chloro-3-((3,3-difluorocyclobutyl)methoxy)phenyl)acetamide (2.44 g,8.42 mmol) The mixture was stirred at 80° C. for two days. The resultingthick red solution was pipetted onto ice, resulting in a yellowprecipitate. The precipitate was collected on a Buchner funnel, washedwith water (˜500 mL), and dried to provide 2.38 g of the title compoundas a pale yellow solid. LCMS and ¹H NMR are consistent with2,6-dichloro-7-((3,3-difluorocyclobutyl)methoxy)quinoline-3-carbaldehyde(2.38 g, 6.88 mmol, 82% yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm10.31-10.36 (m, 1H), 8.88 (s, 1H), 8.48 (s, 1H), 7.65 (s, 1H), 4.37 (d,J=4.69 Hz, 2H), 2.53-2.84 (m, 5H). LCMS (Method 1): m/z 346 [M+H]⁺.

Step-3:6-Chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinoline-3-carbaldehyde

A solution of2,6-dichloro-7-((3,3-difluorocyclobutyl)methoxy)quinoline-3-carbaldehyde(2.66 g, 7.68 mmol) in concentrated HCl (75 mL) was stirred at 100° C.for one day during which time a red crust formed on the surface of theflask. The mixture was diluted with water (800 mL), resulting information of a red precipitate. The mixture was allowed to stand at roomtemperature for 4 days. The precipitate was then collected on a Buchnerfunnel, washed with water (1 L), and dried under vacuum at 50° C. toprovide 2.16 g of the title compound as a red solid. LCMS and ¹H NMR areconsistent with6-chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinoline-3-carbaldehyde(2.16 g, 6.59 mmol, 86% yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.21 (s,1H), 10.16-10.18 (m, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 6.94 (s, 1H), 4.20(d, J=4.10 Hz, 2H), 2.54-2.80 (m, 5H). LCMS (Method 1): m/z+328 [M+H]⁺.

Step-4:(E)-N-((6-Chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of6-chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinoline-3-carbaldehyde(499.6 mg, 1.525 mmol) and 2-methylpropane-2-sulfinamide (222.1 mg,1.832 mmol) was placed in a 25 mL round bottom flask under an atmosphereof nitrogen. THF (3.0 mL) and titanium (IV) isopropoxide (Ti(O^(i)Pr)₄)(0.90 mL, 3.07 mmol) were added by syringe, and the suspension wasstirred at room temperature overnight. Once LCMS indicated nearcompletion of reaction, the reaction was quenched by dropwise additionof saturated aqueous NH₄Cl solution (2 mL). The material was thentriturated with EtOAc (100 mL) and the resulting precipitate wasfiltered through Celite®. The filter cake was washed with EtOAc (50 mL),sonicated in EtOAc for 15 minutes and filtered using a Buchner funnel.The filtrates were combined and washed with brine (100 mL), dried(Na₂SO₄), filtered, and evaporated under reduced pressure to provide 413mg of the title compound as a yellow solid. LCMS and ¹H NMR areconsistent with(E)-N-((6-chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide(413 mg, 0.958 mmol, 62.9% yield)¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.21(s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 6.95 (s, 1H), 4.19(d, J=4.40 Hz, 2H), 2.55-2.79 (m, 5H), 1.19 (s, 9H). LCMS (Method 1):m/z 431 [M+H]⁺.

Step-5:N-(1-(6-Chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

(E)-N-((6-Chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide (411.3 mg, 0.955 mmol) wasplaced in a 100 mL round-bottom flask under an atmosphere of nitrogen.DCM (7.6 mL) was added, and the suspension was cooled on a dryice/chloroform bath (to approx. −60° C.). Methylmagnesium bromide(MeMgBr, 3M in ether) (0.95 mL, 2.85 mmol) was added dropwise. The coldbath was then allowed to warm to room temperature overnight, resultingin an orange solution. Once LCMS indicated reaction completion, thesolution was cooled on an ice bath and treated dropwise with water (5mL), resulting in precipitation. The mixture was diluted with EtOAc (100mL) and washed with water (100 mL). Silica gel was added to the organiclayer and the solvent was evaporated under reduced pressure. Thematerial was purified by column chromatography on a Biotage® MPLCchromatography system (eluted with 0 to 5% MeOH in DCM with isocraticelution at 3.2% MeOH) to provide 345.5 mg of the title compound as abrown brittle foam. LCMS and ¹H NMR are consistent withN-(1-(6-chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(345.5 mg, 0.773 mmol, 81% yield). NMR shows a ˜1:1 mixture ofdiastereomers. LCMS (Method 1): m/z 447 [M+H]⁺.

Step-6:3-(1-Aminoethyl)-6-chloro-7-((3,3-difluorocyclobutyl)methoxy)quinolin-2(1H)-onehydrochloride (II-16)

A solution ofN-(1-(6-chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide(342.7 mg, 0.767 mmol) in MeOH (7.0 mL) was cooled on an ice bath andtreated dropwise with 4M HCl in 1,4-dioxane (4 mL). The solution wasthen stirred for 25 minutes. The solvents were evaporated under reducedpressure at room temperature. The residue was triturated with 20 mLethyl ether and the resulting precipitate was collected on a Hirschfunnel and washed with more ethyl ether to provide 271.4 mg of a pinksolid. LCMS and ¹H NMR are consistent with3-(1-aminoethyl)-6-chloro-7-((3,3-difluorocyclobutyl)methoxy)quinolin-2(1H)-onehydrochloride (271.4 mg, 0.716 mmol, 93% yield)¹H NMR (300 MHz,Methanol-d₄): δ ppm 7.95 (s, 1H), 7.79 (s, 1H), 6.96 (s, 1H), 4.48-4.55(m, 1H), 4.20 (d, J=4.10 Hz, 2H), 2.56-2.79 (m, 5H), 1.68 (d, J=7.04 Hz,3H). LCMS (Method 1): m/z 343 [M+H]⁺.

Example 19—Intermediate II-17:(S)-3-(1-Aminoethyl)-6-chloro-8-fluoroquinolin-2(1H)-one

Step-1: tert-Butyl (4-chloro-2-fluorophenyl)carbamate

A solution of 4-chloro-2-fluoroaniline (2 g, 13.74 mmol) anddi-tert-butyl dicarbonate (6.4 mL, 27.6 mmol) in 1,4-dioxane (50 mL) wasstirred at reflux for 2 days. The solvent was then evaporated. Theresulting oil was diluted with MeOH, water, and aqueous ammoniumhydroxide solution (10 mL each) and vigorously stirred for 45 minutes.The organic lower layer was separated. The organic material was dilutedwith EtOAc (50 mL), and washed with water (50 mL), 3.6% aqueous HClsolution (2×50 mL), saturated aqueous NaHCO₃ solution (50 mL), and thenagain with water (2×50 mL). The organic layer was dried (MgSO₄),filtered, and evaporated under reduced pressure to provide tert-butyl(4-chloro-2-fluorophenyl)carbamate (3.0011 g, 12.22 mmol, 89% yield) asa reddish liquid that solidified on standing. ¹H NMR (300 MHz, DMSO-d₆):δ ppm 9.12 (s, 1H), 7.63 (t, J=8.65 Hz, 1H), 7.42 (dd, J=10.85, 2.35 Hz,1H), 7.18-7.24 (m, 1H), 1.45 (s, 9H). LCMS (Method 1): m/z 246 [M+H]⁺.

Step-2: tert-Butyl (4-chloro-2-fluoro-6-formylphenyl)carbamate

An oven-dried 3-necked 500 mL round bottom flask was fitted with anoven-dried addition funnel and placed under an atmosphere of nitrogen.tert-Butyl (4-chloro-2-fluorophenyl)carbamate (5.44 g, 22.14 mmol) andethyl ether (91 mL) were added by syringe. The clear solution was cooledon an acetonitrile/dry ice bath (to approximately −40° C.).tert-Butyllithium (1.7M in pentane, 33 mL, 22.14 mmol) was added to theaddition funnel by cannula. The t-BuLi solution was added dropwise tothe ether solution (over ˜10 minutes), during which time the ethersolution began to turn orange. The solution was stirred at about ˜40° C.for 2 hours, during which time it progressively became more orange. DMF(8.7 mL, 112 mmol) was added dropwise (over ˜10 minutes), resulting inprecipitation of a yellow solid. The MeCN/dry ice bath was replaced withan ice bath and the mixture was stirred for an additional 2 hours. Thereaction was then quenched by dropwise addition of water (20 mL),resulting in a brown mixture and the ice bath was removed. The mixturewas diluted with EtOAc (100 mL), washed with water (2×100 mL), dried(Na₂SO₄), filtered, and evaporated under reduced pressure to provide5.45 g of an oily black solid. The material was triturated with hexanes(50 mL), collected on a Buchner funnel and washed with more hexanes toprovide 2.73 g tert-butyl (4-chloro-2-fluoro-6-formylphenyl)carbamate asa yellow powder. The filtrate was evaporated under reduced pressure, theresidue was triturated in hexanes (˜15 mL), and the resulting yellowsolid was collected on a Hirsch funnel to provide a second crop of thetitle compound (0.66 g). A total of 3.39 g (12.4 mmol, 56% yield) oftert-butyl (4-chloro-2-fluoro-6-formylphenyl)carbamate was recovered. ¹HNMR (300 MHz, DMSO-d₆): δ ppm 9.93 (d, J=0.88 Hz, 1H), 9.47 (s, 1H),7.81-7.90 (m, 1H), 7.55-7.61 (m, 1H), 1.44 (s, 9H). LCMS (Method 1): m/z296 [M+Na].

Steps-3 & 4: (S)-3-(1-Aminoethyl)-6-chloro-8-fluoroquinolin-2(1H)-onehydrochloride (II-17)

An oven-dried 200 mL round bottom flask and stir bar were placed underan atmosphere of nitrogen. THF (17 mL) and diisopropylamine (1.59 mL,11.16 mmol) were added by syringe. The resulting solution was cooled ona dry ice/acetone bath (to approximately −78° C.) and thenn-butyllithium (1.6M in hexane, 7.1 mL, 11.36 mmol) was added dropwiseover a 5 minute period. After stirring for 15 minutes, a solution of(S)-ethyl 3-((tert-butoxycarbonyl)amino)butanoate K (860.7 mg, 3.72mmol) in THF (3.75 mL) was added dropwise over 5 minutes. The solutionwas stirred for 80 minutes at −78° C., and a solution of tert-butyl(4-chloro-2-fluoro-6-formylphenyl)carbamate (1016.4 mg, 3.71 mmol) inTHF (7.5 mL) was then added dropwise by syringe. The reaction wasstirred at −78° C. for another 22 minutes and then quenched by additionof saturated aqueous NH₄Cl solution (17 mL). The mixture was partitionedbetween EtOAc and water (100 mL each). The organic layer was dried(MgSO₄), filtered, and evaporated under reduced pressure to provide 1.88g of the title compound as an orange gum. The material was dissolved in1,4-dioxane (38 mL) treated with 12M aqueous HCl (0.96 mL), and stirredat 110° C. for 50 minutes. The sample was then allowed to cool. Thesolvent was evaporated under reduced pressure to provide 1.24 g of a redsolid. The material was triturated in IPA (25 mL), collected on a Hirschfunnel and washed sequentially with IPA (5 mL) and ethyl ether (˜20 mL)to provide (S)-3-(1-aminoethyl)-6-chloro-8-fluoroquinolin-2(1H)-onehydrochloride (370.4 mg, 1.337 mmol, 36% yield) as a red solid. ¹H NMR(300 MHz, DMSO-d₆): δ ppm 12.41 (s, 1H), 8.33 (br s, 3H), 8.10 (s, 1H),7.67-7.76 (m, 2H), 4.38-4.53 (m, 1H), 1.52 (d, J=7.04 Hz, 3H). LCMS(Method 1): m/z 241 [M+H]⁺.

Example 20—Intermediate II-18:(S)-3-(1-aminoethyl)-6-chloro-7-isopropoxy quinolin-2(1H)-one

Step-1: 4-Chloro-3-isopropoxyaniline

A mixture of 5-amino-2-chlorophenol (20 g, 139 mmol) and 2-bromopropane(26 mL, 278 mmol) and K₂CO₃ (38.4 g, 278 mmol) in CH₃CN (300 mL) wasrefluxed for 24 h. The reaction mixture was cooled to room temperature,filtered and the solid was washed with ethyl acetate (150 mL). Thefiltrate was concentrated and the residue was purified by ISCO (SiO₂:Hex/EtOAc 0 to 40%) to give the title compound,4-Chloro-3-isopropoxyaniline (22.6 g, 87%).

Step 2: N-(4-Chloro-3-isopropoxyphenyl)acetamide

To a mixture of 4-chloro-3-isopropoxyaniline (22.5 g, 121 mmol) inCH₂Cl₂ (200 mL) was added DIPEA (42 mL, 242 mmol) followed by aceticanhydride (17 mL, 181 mmol). The resultant mixture was stirred at roomtemperature for 3 h. Upon the completion of the reaction, water (100 mL)was added and stirred for 10 minutes. The organic layer was separated,washed with 1N HCl (aq, 200 mL), brine (150 mL) and dried over anhydrousNa₂SO₄. The solution was filtered and concentrated. The crude residuewas recrystallized from CH₂Cl₂/hexanes to give desired compoundN-(4-Chloro-3-isopropoxyphenyl)acetamide (19.6 g, 71%).

Step-3: 2,6-Dichloro-7-isopropoxyquinoline-3-carbaldehyde

DMF (15 mL, 193.6 mmol) was added to a 350 mL seal tube and cooled to 0°C. To this solution was added phosphorous oxychloride (60.1 mL, 645.6mmol) dropwise during 40-50 min. The resultant mixture was brought toroom temperature followed by addition ofN-(4-chloro-3-isopropoxyphenyl)acetamide (14.7 g, 64.5 mmol) in portionsand heated at 80° C. overnight. The mixture was cooled to roomtemperature and carefully poured onto crushed ice. The yellowprecipitate was filtered, washed with water and dried over P₂O₅overnight to afford 2,6-Dichloro-7-isopropoxyquinoline-3-carbaldehyde asyellow solid (17.5 g, 95%).

Step-4: 6-Chloro-7-isopropoxy-2-methoxyquinoline-3-carbaldehyde

To 2,6-dichloro-7-isopropoxyquinoline-3-carbaldehyde (5.8 g, 20.4 mmol)in a co-solvent of MeOH:THF (1:1, 100 mL) was added NaOMe (2.2 g, 40.8mmol) portion wise at rt. The reaction mixture was refluxed for 3 h.After cooling to rt, the reaction was quenched with aqueous NH₄.Clsolution (20 mL). The mixture was extracted with EtOAc (25 mL×3). Thecombined organic layer was dried (Na₂SO₄), concentrated and purified byflash chromatography with Hexane/EA (3:1) to give6-Chloro-7-isopropoxy-2-methoxyquinoline-3-carbaldehyde (5.07 g, 89%) asa yellow solid.

Step-5: 1-(6-Chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethanol

To 6-chloro-7-isopropoxy-2-methoxyquinoline-3-carbaldehyde (5.07 g,18.17 mmol) in THF (100 mL) at −78° C. was added a solution of MeMgCl inTHF (3 M, 9.1 mL, 27.2 mmol) drop wise. The reaction was stirred at roomtemperature (rt) for 3 h and then quenched with aqueous NH₄Cl solution(50 mL). The organic layer was separated and the aqueous layer wasextracted with EtOAc (25 mL×3). The combined organic layers were dried(Na₂SO₄), concentrated, and purified by silica gel chromatography withhexane/EA (3:1) to give compound1-(6-Chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethanol (4.06 g, 76%).

Step-6: 1-(6-Chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethanone

To 1-(6-chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethanol (4.06 g, 13.8mmol) in CH₂Cl₂ (50 mL) at rt was added DMP (7.0 g, 16.5 mmol) portionwise. The reaction was stirred at rt for 2 h, and then was quenched withan aqueous solution of NaHCO₃ and Na₂S20₃. After stirring for 15 min,both layers became clear. The organic layer was separated and theaqueous layer was extracted with CH₂Cl₂ (30 mL×2). The combined organiclayers were dried (Na₂SO₄), concentrated and purified by silica gelchromatography with hexane/EA (4:1) to give1-(6-Chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethanone (3.67 g, 72%)as a white solid.

Step-7:(R,E)-N-(1-(6-chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide

To 1-(6-chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethanone (3.67 g,12.5 mmol) in THF/toluene (20 mL:400 mL) at rt was added(R)-2-methylpropane-2-sulfinamide (3.03 g, 25 mmol,) and Ti(O^(i)Pr)₄(11 mL, 37.5 mmol,). The reaction was refluxed with a Dean-Starkapparatus. After the reaction was refluxed for 4 h and 150 mL of solventwas removed, the reaction was cooled to rt. The solvent was removedunder vacuum, and 50 mL of EtOAc was added to the residue, followed byaddition of 20 mL of saturated aqueous NaHCO₃ solution. After stirringfor 10 min, the solid was removed through a pad of celite. The filtratewas extracted with EtOAc (200 mL×2), dried (Na₂SO₄), concentrated andpurified by silica gel chromatography with hexane/EA (1:1) to give thetitle compound (4.32 g, 87%).

Step-8:(R)—N—((S)-1-(6-chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

To(R,E)-N-(1-(6-chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (4.32 g, 10.9 mmol) in THF (100 mL) at −78° C.,was added 1 M L-selectride (14.2 mL, 14.2 mmol) in THF dropwise. Thereaction mixture was warmed to rt and stirred for 3 h. The reaction wasquenched with aqueous saturated NH₄Cl (30 mL) solution and thenextracted with EtOAc (20 mL×3). The combined organic layers were dried(Na₂SO₄), concentrated and purified by silica gel chromatography withhexane/EA (1:1) to give the desired compound (3.58 g, 82%).

Step-9: (S)-3-(1-aminoethyl)-6-chloro-7-isopropoxyquinolin-2(1H)-onehydrochloride salt (II-18)

To(R)—N—((S)-1-(6-chloro-7-isopropoxy-2-methoxyquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (3.58 g, 8.99 mmol) in dioxane (50 mL) was added 2N HCl (50 mL) at rt. The reaction was refluxed for 3 h. The solvent wasremoved under vacuum and the residue was dried under vacuum to affordcrude II-18, which was further purified by trituration(CH₂Cl₂/MeOH/hexane) to give pure compound II-18 (2.44 g, 86%) as awhite solid. ¹H NMR (300 MHz, DMSO-d6): δ 12.10 (s, 1H), 8.29 (br, s,3H), 7.98 (s, 1H), 7.83 (s, 1H), 7.08 (s, 1H), 4.66 (m, 1H), 4.38 (m,1H), 3.91 (s, 3H), 1.52 (d, J=6.87 Hz, 3H), 1.37 (d, J=6.03 Hz, 6H).LCMS (Method 3, APCI): RT=8.06 min, m/z=281.1 [M+H]⁺.

Example 21—Intermediate III-1:5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile

Step-1: 2-cyano-5-fluoropyridine 1-oxide

A solution of 5-fluoropicolinonitrile (7.27 g, 59.5 mmol) in CHCl₃ (60mL) was added dropwise by addition funnel to a solution of m-CPBA (<77%,22.00 g, 98 mmol) in CHCl3 160 mL). The solution was stirred at reflux 4days, at which time LCMS showed ˜85% conversion. The sample was allowedto cool, then sodium sulfite (12.4 g, 98 mmol) was added and the samplewas stirred at room temperature three hours, during which time thesolution became thick with a white precipitate. The sample was dilutedwith DCM (300 mL) and filtered on a Buchner funnel, and the filter cakewas washed with DCM (˜400 mL). A white material precipitated in thefiltrate. The filtrate mixture was washed with saturated aqueous NaHCO₃(400 mL), during which the solids went into solution. The organic layerwas washed with water (300 mL), then dried (MgSO₄) and filtered. Silicagel was added and the mixture was evaporated under reduced pressure. Thematerial was chromatographed by Biotage MPLC (340 g silica gel column)with 0 to 100% EtOAc in hexanes, with isocratic elution when peaks cameoff to provide 2-cyano-5-fluoropyridine 1-oxide (4.28 g, 31.0 mmol, 52%yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 8.85-8.93 (m,1H), 8.23 (dd, J=9.09, 6.74 Hz, 1H), 7.53-7.64 (m, 1H). LCMS (Method 1):Rt 0.57 min., m/z 138.9 [M+H]⁺.

Step 2: 6-cyano-3-fluoropyridin-2-yl acetate

A solution of 2-cyano-5-fluoropyridine 1-oxide (4.28 g, 31.0 mmol) inacetic anhydride (40 ml, 424 mmol) was heated at reflux (150° C. bath)three days, during which the clear solution turned dark. The sample wasconcentrated under reduced pressure. The residue was dissolved in MeOH(30 mL) and stirred 1 hour. Silica gel was added and the solvent wasevaporated under reduced pressure. The material was chromatographed byBiotage MPLC (100 g silica gel column) with 0 to 23% EtOAc in hexanes toprovide 6-cyano-3-fluoropyridin-2-yl acetate (3.32 g, 18.43 mmol, 60%yield) as a clear liquid that solidified on cooling. ¹H NMR (300 MHz,CHLOROFORM-d): δ ppm 7.65-7.75 (m, 2H), 2.42 (s, 3H). LCMS (Method 1):Rt 1.54 min., m/z 138.8 (loss of acetate).

Step 3: 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile

A solution of 6-cyano-3-fluoropyridin-2-yl acetate (3.32 g, 18.43 mmol)in MeOH (40 ml) was treated with potassium carbonate (5.10 g, 36.9 mmol)and stirred at room temperature four hours. LCMS at 2 hours showed thereaction had gone to completion. The solvent was evaporated underreduced pressure. The residue was dissolved in water (100 mL) andacidified to pH≤1 with 1M HCl. The solution was extracted with EtOAc(3×100 mL). The combined organic extracts were dried (Na₂SO₄), filtered,and evaporated under reduced pressure to provide5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile (2.34 g, 16.94 mmol,92% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.92 (brs, 1H), 7.73 (br s, 1H), 7.43 (br s, 1H). LCMS (Method 1): Rt 0.70 min.,m/z 138.9 [M+H]⁺.

Step 4: 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(III-1)

A mixture of 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile (2.31 g,16.73 mmol) and potassium carbonate (4.86 g, 35.2 mmol) in a 200 mLround bottom flask was treated with DMF (46 ml) and stirred 15 minutes.Mel (1.2 ml, 19.19 mmol) was added and the mixture was stirred at roomtemperature 45 minutes. The solvent was evaporated under reducedpressure. The residue was mixed with water (150 mL) and extracted withDCM (2×150 mL). The combined organic extracts were dried (MgSO₄),filtered, treated with silica gel, and evaporated under reducedpressure, then evaporated further at 60° C. under high vacuum. Thematerial was chromatographed by Biotage MPLC with 0 to 35% EtOAc inhexanes, with isocratic elution at 16% EtOAc and 35% EtOAc while peakscame off. The peak that came off with 16% EtOAc was O-methylatedmaterial and was discarded. The peak that came off with 35% EtOAcprovided the title compound III-1 (1.70 g, 11.17 mmol, 67% yield) as asolid. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 7.53 (dd, J=9.38, 7.62 Hz, 1H),7.18 (dd, J=7.77, 4.84 Hz, 1H), 3.60 (s, 3H). LCMS (Method 1): Rt 0.94min., m/z 152.9 [M+H]⁺.

Example 22—Intermediate V-2:5-amino-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile

Step-1: N-(6-Cyanopyridin-3-yl)-2,2,2-trifluoroacetamide

A solution of 5-aminopicolinonitrile (5.50 g, 46 mmol, 1 eq.) in 300 mLDCM was cooled to 0° C., and then treated with TEA (20 mL, 144 mmol, 3.1eq.) followed by dropwise addition of trifluoroacetic anhydride (20 mL,144 mmol, 3.1 eq.). After stirring overnight at room temperature, thereaction mixture was poured onto ice, and extracted with DCM.Purification by passing over a silica gel plug (hexane/EtOAc, 75/25)provided N-(6-Cyanopyridin-3-yl)-2,2,2-trifluoroacetamide (7.24 g, 73%)as a white solid. TLC: Hexane/EtOAc, 8/2.

Step-2: N-(6-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide-N-oxide

A solution of N-(6-Cyanopyridin-3-yl)-2,2,2-trifluoroacetamide (7.24 g,33.7 mmol, 1 eq.) in 270 mL CHCl₃ was cooled in an ice bath, thentreated dropwise with a solution of mCPBA (7.68 g, 39 mmol, 1.15 eq.) in65 mL CHCl₃. The reaction mixture was refluxed for 24 hours and thenpoured into H₂O. After stirring with 10% aqueous NaHSO₃ and NaHCO₃, thesolid was collected and rinsed with H₂O, then CHCl₃. This provided 1.86g (24%) of the title compound as a white solid. UnreactedN-(6-Cyanopyridin-3-yl)-2,2,2-trifluoroacetamide (4.70 g, 65%) wasrecovered by extraction of the filtrate, and purification bychromatography on silica gel (hexane/EtOAc, 75/25).

Step-3: 5-Amino-6-oxo-1,6-dihydropyridine-2-carbonitrile

A suspension of N-(6-cyanopyridin-3-yl)-2,2,2-trifluoroacetamide-N-oxide(0.81 g, 3.5 mmol, 1 eq.) in 10.5 mL THF was treated with TEA (0.75 mL,5.3 mmol, 1.5 eq.) followed by dropwise addition of trifluoroaceticanhydride (1.74 mL, 12.5 mmol, 3.5 eq.). After stirring overnight atroom temperature, ice chips and 12 mL 10% NaOH were added. Afterstirring at room temperature for 1 hour, the reaction mixture wasacidified to pH˜4 with HOAc and the precipitated solid was collected,providing 0.31 g 5-Amino-6-oxo-1,6-dihydropyridine-2-carbonitrile (64%)as a beige solid. TLC: DCM/MeOH, 97/3.

Step-4: 5-Amino-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (V-2)

A solution of 5-Amino-6-oxo-1,6-dihydropyridine-2-carbonitrile (500 mg,3.7 mmol, 1 eq.) in 18 mL DMF was treated with anhydrous K₂CO₃ (1.0 g,7.26 mmol, 2 eq.) and CH₃I (0.175 mL, 4.0 mmol, 1.1 eq) and stirred atroom temperature for 1.5 h. To the reaction mixture water was addedfollowed by extraction with EtOAc (2×), the extracts were dried (Na₂SO₄)and evaporated to provide a tan solid. Analysis of the crude product byNMR indicated a˜8/2 ratio of desired product vs the O-methylated isomer.Trituration of the solid with Et₂O provided 160 mg of the desiredproduct (29%). Purification of the Et₂O washes by C18 ISCO preparativechromatography provided an additional 82 mg of the title compound V-1 asthe TFA salt (15%). TLC: Hexane/EtOAc, 1/1. ¹H-NMR (300 MHz, d₆DMSO) δ:6.94 (d, J=7.68), 6.42 (broad s, 2H), 6.33 (d, J=7.68), 3.55 (s, 3H).LC/MS (Methods 3): Rt 3.0 min., m/z 150 [M+H]⁺.

TABLE 1 The Intermediates listed in Table 1 were either prepared usingthe methods described above or obtained from commercial sources. Inter-mediate No. Chemical names Structure II-1 (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one

II-2 (R)-3-(1-aminoethyl)-6- chloroquinolin-2(1H)- one

II-3 3-(1-aminoethyl)-6-chloro- 7-fluoroquinolin-2(1H)- one

II-4 (S)-3-(1-aminoethyl)-6- chloro-7-fluoroquinolin- 2(1H)-one

II-5 (R)-3-(1-aminoethyl)-6- chloro-7-fluoroquinolin- 2(1H)-one

II-6 3-(1-aminoethyl)-6-chloro- 7-methoxyquinolin-2(1H)- one

II-7 (S)-3-(1-aminoethyl)-6- chloro-7-methoxyquino- lin-2(1H)-one

II-8 (R)-3-(1-aminoethyl)-6- chloro-7-methoxyquino- lin-2(1H)-one

II-9 3-(1-aminoethyl)-6-chloro- 7-(pyridin-2-ylmethoxy)-quinolin-2(1H)-one

II-10 (S)-3-(1-aminoethy)-6- chloro-7-(pyridin-2-yl-methoxy)quinolin-2(1H)- one

II-11 (S)-3-(1-aminoethyl)-6- chloro-1,8-naphthyridin- 2(1H)-one

II-12 (R)-3-(1-aminoethyl)-6- chloroquinoxalin-2(1H)- one

II-13 (S)-3-(1-aminoethyl)-6- chloroquinoxalin-2(1H)- one

II-14 (3-((S)-1-aminoethyl)-6- chloro-7-((R)-1-(pyridin-2-yl)ethoxy)quinolin- 2(1H)-one

II-15 (S)-3-(1-aminoethyl)-6- chloro-7-(cyclopropyl- methoxy)quinolin-2(1H)-one

II-16 3-(1-aminoethyl)-6-chloro- 7-(3,3-difluorocyclobutyl)-methoxy)quinolin-2(1H)- one

II-17 (S)-3-(1-aminoethyl)-6- chloro-8-fluoroquinolin- 2(1H)-one

II-18 (S)-3-(1-aminoethyl)-6- chloro-7-isopropoxy quinolin-2(1H)-one

III-1 5-fluoro-1-methyl-6-oxo- 1,6-dihydropyridine-2- carbonitrile

III-2 3-fluoro-1-methylpyridin- 2(1H)-one

IV-1 6-chloro-2-oxo-1,2- dihydroquinoline-3- carbaldehyde

IV-2 6-chloro-7-methoxy-2- oxo-1,2-dihydroquinoline- 3-carbaldehyde

IV-3 6-chloro-2-oxo-7- (pyridin-2-ylmethoxy)- 1,2-dihydroquinoline-3-carbaldehyde

V-1 3-amino-1-methylpyridin- 2(1H)-one

V-2 5-amino-1-methyl-6-oxo- 1,6-dihydropyridine-2- carbonitrile

Note: All amines are hydrochloride salts, except that II-5a is TFA salt

Example23—5-(((6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-1)

To a 100 mL round bottle flask was added6-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde IV-1 (69.6 mg, 0.335mmol), 5-amino-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile V-2 (50mg, 0.335 mmol) and acetic acid (0.096 ml, 1.676 mmol) in DCM (10 ml).Finally sodium triacetoxyborohydride (107 mg, 0.503 mmol) was chargedand stir vigorously at room temperature under N₂ flow overnight. Thereaction mixture was diluted with EtOAc (60 mL), then washed withsaturated NaHCO₃, water (×2) and brine. The organic extract was driedover Na₂SO₄, filtered and concentrated to yield a crude, which waspurified by reverse phase preparative HPLC on Gilson to yield a mixtureof product and unknown by-product (˜32 mg, 28% yield, 81% HPLC purity).The mixture was subjected 2nd HPLC purification to afford a pure desiredproduct (4 mg, 3.5% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.97 (s, 1H),7.56 (br s, 1H), 7.45 (br d, J=11.43 Hz, 2H), 7.36 (br d, J=8.79 Hz,1H), 7.12-7.20 (m, 1H), 6.66-6.78 (m, 1H), 6.00 (br d, J=7.92 Hz, 1H),3.68 (s, 2H), 3.31 (br s, 3H). LCMS (Method 1): Rt 2.37 min, m/z 340.97[M+H]⁺.

Example24—6-chloro-3-((1-ethyl-2-oxo-1,2-dihydropyridin-3-ylamino)methyl)quinolin-2(1H)-one(I-2)

Step 1: 1-ethyl-3-nitropyridin-2(1H)-one

A mixture of 3-nitropyridin-2(1H)-one (1.00 g, 7.14 mmol) and K₂CO₃(3.00 g, 21.71 mmol) in DMF (30 ml) was treated with ethyl iodide (0.60ml, 7.42 mmol) and stirred at 50° C. overnight. LCMS indicated a 4:1mixture of product and starting material. More ethyl iodide (0.25 mL)was added and the reaction was stirred at 60° C. five hours. The yellowmixture was diluted with water (100 mL) and extracted with EtOAc (3×100mL). The combined organic extracts were dried (MgSO4), filtered, andevaporated under reduced pressure to provide 1.08 g yellow solid. Thematerial was dissolved in a few mL DCM and chromatographed by BiotageMPLC (25 g silica gel column, 0 to 10% MeOH in DCM, with isocraticelution at 3% MeOH) to provide 1-ethyl-3-nitropyridin-2(1H)-one (898.9mg, 5.35 mmol, 74.9% yield) as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆): δ ppm 8.38 (dd, J=7.92, 2.05 Hz, 1H), 8.24 (dd, J=6.60, 2.20Hz, 1H), 6.44 (dd, J=7.62, 6.45 Hz, 1H), 4.05 (q, J=7.04 Hz, 2H), 1.26(t, J=7.18 Hz, 3H). LCMS (Method 1): Rt 0.96 min., m/z 169.0 [M+H]⁺.

Step 2: 3-amino-1-ethylpyridin-2(1H)-one

A solution of 1-ethyl-3-nitropyridin-2(1H)-one (891.2 mg, 5.30 mmol) andtin (II) chloride dihydrate (5.03 g, 22.29 mmol) in EtOAc (30 ml) in a200 mL round bottom flask was stirred at 80° C. two hours; LCMS at 1.5hours showed the reaction had gone cleanly to completion. The solutionwas allowed to cool and was diluted with EtOAc (50 mL), then NaHCO₃ (8g) was added in small portions and the mixture was stirred 20 minutes,by which time little effervescence had occurred and the mixture wasstill strongly acidic (pH ˜1). Water (50 mL) was added in portions withthorough stirring, first magnetically and then by hand as a precipitateformed, resulting in a dark blue mixture of pH ˜8. The mixture wasfiltered on a Buchner funnel and the filter cake was washed with severalportions of EtOAc (˜100 mL total). The filtrate layers were separated.The aqueous phase was extracted with EtOAc (3×50 mL), and all theorganics were combined and dried (Na₂SO₄), filtered, and evaporatedunder reduced pressure. The resulting bluish solid (0.64 g) wasdissolved in a few mL DCM and chromatographed by Biotage MPLC (25 gsilica gel snap column, 0 to 9% MeOH in DCM, with isocratic elution at3.8% MeOH). The blue solid thus obtained was dissolved in DCM, treatedwith silica gel, and evaporated under reduced pressure. The material wasrechromatographed by Biotage MPLC (25 g silica gel column, 0 to 100%EtOAc in hexanes, with isocratic elution at 67% EtOAc) to provide3-amino-1-ethylpyridin-2(1H)-one (517.7 mg, 3.75 mmol, 70.7% yield) as aslightly blue solid. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 6.88 (dd, J=6.89,1.91 Hz, 1H), 6.41 (dd, J=7.04, 1.76 Hz, 1H), 6.03 (dd, J=6.90, 6.90 Hz,1H), 5.06 (s, 2H), 3.89 (q, J=7.13 Hz, 2H), 1.19 (t, J=7.18 Hz, 3H).LCMS (Method 1): Rt 0.76 min., m/z 139.0 [M+H]⁺.

Step 3:6-chloro-3-((1-ethyl-2-oxo-1,2-dihydropyridin-3-ylamino)methyl)quinolin-2(1H)-one(I-2)

A suspension of 6-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde(100.1 mg, 0.482 mmol) and 3-amino-1-ethylpyridin-2(1H)-one (67.1 mg,0.486 mmol) in MeOH (1.5 mL) and toluene (1.5 mL) was treated with AcOH(27.6 μL) and shaken at 50° C. for 5.5 hours, during which the bluecolor of the pyridinone starting material was discharged. The solventswere evaporated under reduced pressure. The red residue was treated withsuccessively with two aliquots of toluene (3 mL each) and evaporatedunder reduced pressure. The residue was suspended in DCM (3 mL) andtreated with AcOH (135.4 μL) and sodium triacetoxyborohydride (164.3 mg,0.775 mmol) then placed under nitrogen and stirred at room temperatureovernight; within a few minutes the material went into solution, andwithin an hour a material precipitated out. The sample was diluted withDCM/MeOH/EtOAc, treated with silica gel, and evaporated under reducedpressure. The material was chromatographed by Biotage MPLC (0 to 100%EtOAc in hexanes) to provide the title compound (I-2) (25.7 mg, 0.078mmol, 16.16% yield, HPLC purity 100% at 220 nm) as a greenish solid ¹HNMR (300 MHz, DMSO-d₆): δ ppm 12.02 (s, 1H), 7.79 (d, J=2.05 Hz, 1H),7.65 (s, 1H), 7.49 (dd, J=8.65, 2.20 Hz, 1H), 7.30 (d, J=8.79 Hz, 1H),6.90 (dd, J=4.30, 4.30 Hz, 1H), 5.95-6.11 (m, 3H), 4.16 (d, J=5.90 Hz,2H), 3.93 (q, J=6.84 Hz, 2H), 1.22 (t, J=7.04 Hz, 3H). LCMS (Method 4):Rt 1.15 min., m/z 330.0 [M+H]⁺.

TABLE 2 The compounds listed in Table 2 were prepared using methodssimilar to those described for the preparation of I-1 & I-2.

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

TABLE 3 LCMS signal and NMR chemical shifts of each compound listed inTable 2. Cmpd no LCMS 1H NMR (300 MHz) δ ppm Chemical Name I-1 m/z:340.93 1H NMR (300 MHz, CHLOROFORM-d) δ 5-{[(6-chloro-2-oxo-1,2- (M +H)+ ppm 7.97 (s, 1 H), 7.56 (br s, 1 H), 7.45 dihydroquinolin-3- Rt(min): 1.76 (br d, J = 11.43 Hz, 2 H), 7.36 (br d,yl)methyl]amino}-1-methyl-6- J = 8.79 Hz, 1 H), 7.12-7.20 (m, 1 H),oxo-1,6-dihydropyridine-2- 6.66-6.78 (m, 1 H), 6.00 (br d, J = 7.92carbonitrile Hz, 1 H), 3.68 (s, 2 H), 3.31 (br s, 3 H). I-2 m/z: 329.991H NMR (300 MHz, DMSO-d6): δ ppm 6-chloro-3-{[(1-ethyl-2-oxo- (M + H)+12.02 (s, 1 H), 7.79 (d, J = 2.05 Hz, 1 H), 1,2-dihydropyridin-3- Rt(min): 1.15 7.65 (s, 1 H), 7.49 (dd, J = 8.65, 2.20 Hz, 1yl)amino]methyl}-1,2- H), 7.30 (d, J = 8.79 Hz, 1 H), 6.90 (dd,dihydroquinolin-2-one J = 4.30, 4.30 Hz, 1 H), 5.95-6.11 (m, 3 H), 4.16(d, J = 5.90 Hz, 2 H), 3.93 (q, J = 6.84 Hz, 2 H), 1.22 (t, J = 7.04 Hz,3 H). I-3 m/z: 315.98 1H NMR (300 MHz, CHLOROFORM-d) δ6-chloro-3-{[(1-methyl-2-oxo- (M + H)+ ppm 11.42 (br s, 1 H), 7.58 (s, 1H), 7.41 1,2-dihydropyridin-3- Rt (min): 1.06 (d, J = 2.05 Hz, 1 H),7.31-7.38 (m, 1 H), yl)amino]methyl}-1,2- 7.21-7.27 (m, 1 H), 6.62 (d, J= 6.45 Hz, 1 dihydroquinolin-2-one H), 6.13 (br s, 1 H), 5.95-6.04 (m, 1H), 4.34 (s, 2 H), 3.55 (s, 4 H). I-4 m/z: 327.04 1H NMR (300 MHz,DMSO-d6 ): δ 5-{[(6-chloro-2-oxo-1 2- (M + H)+ 12.01 (br, 1H), 7.74(s,1H), 7.55(s, 1H), dihydroquinolin-3- Rt (min): 1.01 7.45(dd, J1 = 2.35Hz, J2 = 8.8 Hz, 1H), yl)methyl]amino}-6-oxo-1,6- 7.27(d, J = 8.79 Hz,1H), 6.60-6.80(m, 2H),, dihydropyridine-2-carbonitrile 6.00(d, J = 7.62Hz, 1H), 4.17(d, J = 6.16 Hz, 2H) I-5 m/z: 342.016-chloro-3-{[(1-cyclopropyl-2- (M + H)+ oxo-1,2-dihydropyridin-3- Rt(min): 1.15 yl)amino]methyl}-1,2- dihydroquinolin-2-one I-6 m/z: 329.991H NMR (300 MHz, DMSO-d6): δ ppm 6-chloro-3-{[(1,6-dimethyl-2- (M + H)+12.00 (s, 1 H), 7.77 (d, J = 2.35 Hz, 1 H), oxo-1,2-dihydropyridin-3- Rt(min): 1.13 7.62 (s, 1 H), 7.48 (dd, J = 8.79, 2.35 Hz, 1yl)amino]methyl}-1,2- H), 7.30 (d, J = 8.79 Hz, 1 H), 5.98-6.04dihydroquinolin-2-one (m, 1 H), 5.88-5.95 (m, 1 H), 5.78 (t, J = 6.30Hz, 1 H), 4.14 (d, J = 6.20 Hz, 2 H), 3.47 (s, 3 H), 2.22 (s, 3 H). I-7m/z: 379.86 1H NMR (300 MHz, DMSO-d6 ): δ 3-{[(6-bromo-2-oxo-1,2- (M +H)+ 12.00(br, 1H), 7.76(d, J = 2.32 Hz, 1H), dihydropyridin-3- Rt (min):0.97 7.59((s, 1H)), 7.45(dd, yl)amino]methyl}-6-chloro-1,2- J1 = 2.40Hz, J2 = 8.78 Hz, 1H), 7.27(d, dihydroquinolin-2-one J = 8.72 Hz, 1H),6.42(br, 1H), 6.18(br, 1H), 5.89(br,1H), 5.82(d, J = 8.98 Hz, 1H)4.13(d, J = 5.38 Hz, 2H) I-8 m/z: 369.90 6-chloro-3-({[2-oxo-6- (M + H)+(trifluoromethyl)-1,2- Rt (min): 1.2 dihydropyridin-3-yl]amino}methyl)-1,2- dihydroquinolin-2-one I-9 m/z: 383.936-chloro-3-({[1-methyl-2-oxo- (M + H)+ 6-(trifluoromethyl)-1,2- Rt(min): 1.43 dihydropyridin-3- yl]amino}methyl)-1,2-dihydroquinolin-2-one I-10 m/z: 359.99 methyl 5-{[(6-chloro-2-oxo-1,2-(M + H)+ dihydroquinolin-3- Rt (min): 1.01 yl)methyl]amino}-6-oxo-1,6-dihydropyridine-3-carboxylate I-11 m/z: 346.04 1H NMR (300 MHz,DMSO-d6): δ ppm 6-chloro-7-methoxy-3-{[(1- (M + H)+ 11.88 (s, 1 H), 7.78(s, 1 H), 7.58 (s, 1 H), methyl-2-oxo-1,2- Rt (min): 1.05 6.94 (s, 1 H),6.88 (dd, J = 6.45, 2.05 Hz, 1 dihydropyridin-3- H), 5.92-6.10 (m, 3 H),4.12 (d, J = 6.45 yl)amino]methyl}-1,2- Hz, 2 H), 3.87 (s, 3 H), 3.45(s, 3 H). dihydroquinolin-2-one I-12 6-chloro-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3- yl)amino]methyl}-7-(pyridin-2- ylmethoxy)-1,2-dihydroquinolin-2-one a. LCMS data are determined by Method 4. b. Datais not available.

Example25—(S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-13)

A mixture of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrileIII-1 (1.23 g, 8.09 mmol),(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride II-1 (1.91g, 7.37 mmol) and N,N-diisopropylethylamine (3.8 mL, 21.8 mmol) inanhydrous dimethyl sulfoxide (57 mL) under N₂ was heated to 110° C. andstirred for 6 hours. After cooling to room temperature, the mixture waspartitioned between EtOAc/H₂O (750 mL/750 mL). The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuum. The residue waspurified on ISCO twice (40 g silica gel column, EtOAc/hexanes 0˜100%; 80g silica gel column, MeOH/dichloromethane 0˜5%). The colorless fractionswere combined and dichloromethane was removed under reduced pressure onrotavap until a lot of white solid precipitated out. The white solid wascollected by filtration and washed with cold MeOH. It was then mixedwith MeCN/H₂O (10 mL/25 mL) and lyophilized to afford the title compoundI-13 as a white solid (790 mg). m.p. 262-264° C. ¹H NMR (300 MHz,DMSO-d₆) δ: 12.07 (s, 1H), 7.75 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.51(dd, J=8.6, 2.3 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H),6.93 (d, J=7.7 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.58 (s,3H), 1.50 (d, J=6.6 Hz, 3H). LCMS (Method 3): 100% pure @ 254 nm, Rt10.78 min, m/z 355, 357 [M+H]⁺. The filtrate and the colored fractions(TLC pure) from the second ISCO were combined and treated with activatedcharcoal and filtered (until the filtrate is colorless). The filtratewas then concentrated under reduced pressure on rotavap to removedichloromethane until a lot of white solid precipitated out. The whitesolid was collected by filtration and washed with cold MeOH. It was thenmixed with MeCN/H₂O (10 mL/25 mL) and lyophilized to afford the titlecompound I-13 as a white solid (970 mg). m.p. 262-264° C. ¹H NMR (300MHz, DMSO-d₆) δ: 12.06 (s, 1H), 7.75 (s, 1H), 7.73 (d, J=2.5 Hz, 1H),7.51 (dd, J=8.6, 2.3 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.0 Hz,1H), 6.92 (d, J=8.0 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.58(s, 3H), 1.50 (d, J=6.9 Hz, 3H). LCMS (Method 3): 100% pure @ 254 nm,m/z 355, 357 [M+H]⁺. The total yield for combined two batches is 67%.

Example26—(S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-14)

A mixture of DIEA (0.165 ml, 0.943mmol)(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one II-1 (70 mg, 0.314mmol) and 5-fluoro-6-oxo-1,6-dihydropyridine-2-carbonitrile (52.1 mg,0.377 mmol) in DMSO (1 ml) was heated to 110° C. for 2 hrs. The reactionmixture was cooled to room temperature, then was treated with EtOAc,washed with water twice, dried and concentrated. The biotagepurification with 0 to 10% MeOH/DCM on a 10 g column afforded(S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-6-oxo-1,6-dihydropyridine-2-carbonitrile (12.1 mg, 11.3%). ¹H NMR (300 MHz, DMSO-d₆) δppm 12.03 (s, 1H), 7.72 (s, 2 H), 7.47 (m, 1H), 7.28 (m, 1H), 6.84 (m,1H), 6.68 (m, 1H), 5.93 (m, 1H), 4.66 (m, 1H), 1.45 (d, J=6.74 Hz, 3H).LCMS (Method 3): Rt 2.35 min, m/z 361.05 [M+Na]⁺.

Example27—(S)-5-((1-(6-Chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-16)

A mixture of (S)-3-(1-aminoethyl)-6-chloro-7-fluoroquinolin-2(1H)-onehydrochloride II-4 (1.00 g, 3.61 mmol),5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile III-1 (604mg, 3.97 mmol), N,N-diisopropylethylamine (1.9 mL, 10.8 mmol) in DMSO(15 mL) was heated at 110° C. in a seal tube for 16 h. MS and TLC showedclean conversion. The reaction mixture was poured into water (300 mL)with vigorous stirring. The solid was filtered and washed by water, andthen dissolved in EtOAc and dried over sodium sulfate. After filtration,the solution was concentrated with silica gel and purified by flashcolumn chromatography (SiO₂: dichloromethane/EtOAc 0 to 50%) to affordthe target compound I-16 as a pale yellow solid (1.20 g, 89%). ¹H NMR(300 MHz, DMSO-d₆) δ 12.12 (s, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.74 (s,1H), 7.21 (d, J=10.4 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 6.92 (d, J=7.4 Hz,1H), 5.94 (d, J=8.2 Hz, 1H), 4.69-4.62 (m, 1H), 3.58 (s, 3H), 1.49 (d,J=6.6 Hz, 3H); LCMS (Method 3): Rt 5.00 min, m/z 373.1, 375.1 [M+H]⁺.

Example28—(S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyrazine-2-carbonitrile(I-17)

Step 1: 6-bromo-3-chloro-1-methylpyrazin-2(1H)-one

A mixture of 6-bromo-3-chloropyrazin-2(1H)-one (2 g, 9.55 mmol) andpotassium carbonate (2.77 g, 20.04 mmol) in a 200 mL round bottom flaskwas treated with DMF (25 ml) and stirred 15 minutes. Mel (0.69 ml, 11.04mmol) was added and the mixture was stirred at room temperature for 45minutes. The solvent was evaporated under reduced pressure. The residuewas mixed with water (75 mL) and extracted with DCM (2×75 mL). Thecombined organic extracts were dried (MgSO₄), filtered, treated withsilica gel, and evaporated under reduced pressure, then evaporatedfurther at 60° C. under high vacuum. The material was chromatographed byBiotage MPLC (silica gel, 0 to 35% EtOAc in hexanes), with isocraticelution at 16% EtOAc and 30% EtOAc while peaks of the desired mass cameoff. The peak that came off with 30% EtOAc provided6-bromo-3-chloro-1-methylpyrazin-2(1H)-one (1.30 g, 5.82 mmol, 61%yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 7.50 (s, 1H),3.63 (s, 3H). LCMS (Method 1): Rt 1.44 min., m/z 222.9, 224.9 [M+H]⁺.

Step 2:(S)-3-(1-((5-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)ethyl)-6-chloroquinolin-2(1H)-one

A mixture of (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-onehydrochloride II-1 (200 mg, 0.772 mmol) and6-bromo-3-chloro-1-methylpyrazin-2(1H)-one (189.2 mg, 0.847 mmol) inDMSO (5 ml) was treated with DIEA (400 μL, 2.290 mmol) and stirred at110° C. five hours. The sample was mixed with water (75 mL) andextracted with DCM (2×50 mL). The combined organic layers were dried(Na₂SO₄) and filtered, silica gel was added, and the solvent wasevaporated under reduced pressure. The sample was chromatographed byBiotage MPLC (25 g silica gel column, 0 to 100% EtOAc in hexanes, withisocratic elution when peaks came off) to provide(S)-3-(1-((5-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)ethyl)-6-chloroquinolin-2(1H)-one (32.9 mg, 0.080 mmol, 10% yield) as an orange solid¹H NMR (300 MHz, DMSO-d₆): δ ppm 11.99 (s, 1H), 7.70-7.75 (m, 2H), 7.56(d, J=7.92 Hz, 1H), 7.46-7.52 (m, 1H), 7.30 (d, J=8.79 Hz, 1H),6.88-6.96 (m, 1H), 5.02-5.17 (m, 1H), 3.50-3.60 (m, 3H), 1.44 (d, J=6.74Hz, 3H). LCMS (Method 1): Rt 2.55 min., m/z 410.8 [M+H]⁺.

Step 3:(S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyrazine-2-carbonitrile(I-17)

A mixture of(S)-3-(1-((5-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)amino)ethyl)-6-chloroquinolin-2(1H)-one(31.0 mg, 0.076 mmol) Pd₂(dba)₃ (7.4 mg, 8.08 μmol) 1,1′-bis(diphenylphosphino)ferrocene (8.7 mg, 0.016 mmol) and dicyanozinc(18.1 mg, 0.154 mmol) was placed under nitrogen in a 2-dram vial. DMF(1.4 ml) was added by syringe. The atmosphere was evacuated and replacedwith nitrogen three times. The mixture was stirred at room temperatureovernight. LCMS indicated the reaction had gone cleanly to completion.The solvent was evaporated under reduced pressure. The residue waspartitioned between water (15 mL) and DCM (2×15 mL). The combinedorganic extracts were dried (Na₂SO₄) and filtered, silica gel was added,and the solvent was evaporated under reduced pressure. The material waschromatographed by Biotage MPLC (0 to 65% EtOAc in hexanes, withisocratic elution when peaks came off) to provide the title compoundI-17 (20.1 mg, 0.055 mmol, 72.0% yield, HPLC purity 96.5% at 220 nm) asan orange solid ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.03 (s, 1H), 8.59 (d,J=8.50 Hz, 1H), 7.77 (s, 1H), 7.72 (d, J=2.35 Hz, 1H), 7.47-7.55 (m,2H), 7.31 (d, J=8.79 Hz, 1H), 5.18-5.31 (m, 1H), 3.48 (s, 3H), 1.48 (d,J=6.74 Hz, 3H). LCMS (Method 4): Rt 1.25 min., m/z 356.1 [M+H]⁺.

Example29—(S)-5-((1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-20)

A mixture of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrileIII-1 (58 mg, 0.38 mmol),(S)-3-(1-aminoethyl)-6-chloro-7-methoxyquinolin-2(1H)-one hydrochlorideII-7 (100 mg, 0.35 mmol) and N,N-diisopropylethylamine (180 μL, 1.04mmol) in n-BuOH (3 mL) was heated to 110′C in a sealed tube under N₂ andstirred overnight. The mixture was then concentrated under reducedpressure and the residue was purified on ISCO (20 g silica gel column,EtOAc/hexanes 0-100%). The off-white solid obtained was triturated withEtOAc/hexanes, filtered, dissolved in hot MeCN/H₂O (10 mL/10 mL) andthen lyophilized to afford the title compound I-20 as a white solid (78mg, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ: 11.90 (s, 1H), 7.74 (s, 1H), 7.68(s, 1H), 6.98 (d, J=7.7 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J=7.9 Hz, 1H),5.95 (d, J=7.9 Hz, 1H), 4.65 (m, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 1.48(d, J=6.9 Hz, 3H). LCMS (Method 3): Rt 4.98 min, m/z 385 [M+H]⁺.

Example30—5-(((S)-1-(6-chloro-2-oxo-7-((R)-1-(pyridin-2-yl)ethoxy)-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-26)

A mixture of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrileIII-1 (35.2 mg, 0.231 mmol) and3-((S)-1-aminoethyl)-6-chloro-7-((R)-1-(pyridin-2-yl)ethoxy)quinolin-2(1H)-onehydrochloride II-14 (80 mg, 0.210 mmol) II-8 was treated with DMSO (1.5ml) and DIEA (111 μL, 0.636 mmol). The solution was stirred at 110° C.for five hours. The sample was mixed with water (20 mL) and extractedwith DCM (2×15 mL). The extracts were washed with water (2×20 mL), dried(Na₂SO₄) and filtered, silica gel was added, and the solvent wasevaporated under reduced pressure. The material was chromatographed byBiotage MPLC (10 g silica gel column) with 0 to 3.4% MeOH in hexanes.The material thus obtained was dissolved in MeCN (2 mL), treated withwater (1 mL), frozen on a dry ice/acetone bath, and lyophilized toprovide the title compound (I-26) (32.7 mg, 0.069 mmol, 33% yield, HPLCpurity 100% at 220 nm) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δppm 11.75 (s, 1H), 8.55-8.62 (m, 1H), 7.80 (dd, J=7.50, 7.50 Hz, 1H),7.74 (s, 1H), 7.64 (s, 1H), 7.39 (d, J=7.62 Hz, 1H), 7.32 (dd, J=7.48,4.84 Hz, 1H), 6.96 (d, J=7.62 Hz, 1H), 6.82-6.89 (m, 2H), 5.93 (d,J=7.92 Hz, 1H), 5.50 (q, J=6.16 Hz, 1H), 4.61 (s, 1H), 3.57 (s, 3H),1.66 (d, J=6.16 Hz, 3H), 1.44 (d, J=6.74 Hz, 3H). LCMS (Method 1): Rt2.61 min., m/z 475.9 [M+H]⁺.

Example31—(S)-5-((1-(6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-27)

A solution of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrileIII-1 (18.3 mg, 0.120 mmol) and(S)-3-(1-aminoethyl)-6-chloro-7-(cyclopropylmethoxy)quinolin-2(1H)-onehydrochloride II-15 (35 mg, 0.106 mmol) was treated with DMSO (0.8 ml)and DIEA (57 μL, 0.326 mmol). The solution was stirred at 110° C. for3.5 hours. The sample was mixed with water (20 mL) and extracted withDCM (2×10 mL). The combined extracts were washed with water (2×20 mL),dried (Na₂SO₄) and filtered, silica gel was added, and the solvent wasevaporated under reduced pressure. The material was chromatographed byBiotage MPLC (10 g silica gel column) with 0 to 70% EtOAc in hexanes.The material thus obtained was dissolved in MeCN (0.8 mL), treated withwater (0.4 mL), frozen on a dry ice/acetone bath, and lyophilized toprovide the title compound (I-27) (23.9 mg, 0.056 mmol, 52.9% yield,HPLC purity >99% at 220 nm) as a white solid. ¹H NMR (300 MHz, DMSO-d₆):δ ppm 11.83 (s, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 6.97 (d, J=7.92 Hz,1H), 6.92 (s, 1H), 6.89 (d, J=7.92 Hz, 1H), 5.95 (d, J=7.92 Hz, 1H),4.61-4.70 (m, 1H), 3.92 (d, J=6.74 Hz, 2H), 3.58 (s, 3H), 1.48 (d,J=6.74 Hz, 3H), 1.21-1.33 (m, 1H), 0.56-0.65 (m, 2H), 0.34-0.44 (m, 2H).LCMS (Method 1): Rt 2.61 min., m/z 424.9 [M+H]⁺.

Example32—5-((1-(6-chloro-7-((3,3-difluorocyclobutyl)methoxy)-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-28)

A mixture of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrileIII-1 (26.7 mg, 0.176 mmol) and3-(1-aminoethyl)-6-chloro-7-((3,3-difluorocyclobutyl)methoxy)quinolin-2(1H)-onehydrochloride II-16 (59.7 mg, 0.157 mmol) was treated with DMSO (1 ml)and DIEA (84 μL, 0.481 mmol). The solution was stirred at 110° C. eighthours. LCMS indicated the reaction had gone to completion. The samplewas mixed with water (15 mL) and extracted with DCM (3×10 mL). Theextracts were dried (Na₂SO₄), filtered, treated with silica gel, andevaporated under reduced pressure. The material was chromatographed byBiotage MPLC (10 g silica gel column, 0 to 75% in EtOAc in hexanes) toprovide the title compound I-28 (40.5 mg, 0.085 mmol, 54.2% yield, HPLCpurity 100% at 220 nm) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6):δ ppm 11.90 (s, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 6.97 (d, J=7.62 Hz,1H), 6.94 (s, 1H), 6.91 (d, J=7.62 Hz, 1H), 5.95 (d, J=7.62 Hz, 1H),4.65 (quin, J=6.82 Hz, 1H), 4.12 (d, J=4.10 Hz, 2H), 3.58 (s, 3H),2.52-2.80 (m, 5H), 1.48 (d, J=6.74 Hz, 3H). LCMS (Method 4): Rt 1.51min., m/z 475.1 [M+H]⁺.

Example33—(S)-5-((1-(6-chloro-7-isopropoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (I-29)

A mixture of(S)-3-(1-aminoethyl)-6-chloro-7-isopropoxyquinolin-2(1H)-onehydrochloride II-18 (128 mg, 0.4 mmol, 1 eq.),5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (67 mg, 0.44mmol, 1.1 eq.) and DIPEA (148 mg, 1.2 mmol, 3 eq.) in 4 mL DMSO washeated at 130-135° C. for 80 minutes. The reaction mixture was thenpoured into water and the resulting solid collected and rinsed withwater. Chromatography on 3.5 g silica gel using a DCM to DCM/EtOH (98/2)gradient followed by trituration with H₂O/MeOH afforded I-29 (93 mg,56%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ: 11.80 (broad s,0.7H), 7.72 (s, 1H), 7.66 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.89 (d,J=7.41, 1H), 5.93 (d, J=7.68, 1H), 4.62 (m, 2H), 3.57 (s, 3H), 1.47 (d,J=7.41, 3H), 1.33 (d, J=6.03, 6H). LC/MS (Method 3), Rt 5.5 min, m/z 413[M+H]⁺.

Example34—(S)-5-((1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-30)

A solution of (S)-3-(1-aminoethyl)-6-chloro-8-fluoroquinolin-2(1H)-onehydrochloride II-17 (91.7 mg, 0.331 mmol) and5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile III-1 (56.8mg, 0.373 mmol) in DMSO (2.0 ml) was treated with DIEA (172 μl, 0.985mmol) and stirred at 110° C. for four hours. The sample was added towater (30 mL), and the resulting precipitate was extracted with DCM(2×20 mL) and EtOAc (10 mL). The combined organic extracts were dried(Na₂SO₄), filtered, treated with silica gel, and evaporated underreduced pressure. The material was chromatographed by Biotage MPLC (10 gsilica gel column) with 0 to 45% EtOAc in hexanes, with isocraticelution when peaks came off. Product fractions were combined, washedwith water (2×30 mL), and evaporated under reduced pressure. The residuewas dissolved in MeCN (4 mL) and water (2 mL), frozen (dry ice & acetonebath), and lyophilized to provide the title compound I-30 (62.0 mg,0.166 mmol, 50.3% yield, HPLC purity 100% at 220 nm) as a grayish-yellowsolid. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 12.15 (s, 1H), 7.77 (s, 1H),7.56-7.65 (m, 2H), 6.97 (d, J=7.92 Hz, 1H), 6.93 (d, J=7.62 Hz, 1H),5.94 (d, J=7.92 Hz, 1H), 4.61-4.75 (m, 1H), 3.58 (s, 3H), 1.50 (d,J=6.74 Hz, 3H). LCMS (Method 1): Rt 2.39 min., m/z 373.0 [M+H]⁺.

Example35—(S)-5-((1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-31)

The mixture of (S)-3-(1-aminoethyl)-6-chloro-1,8-naphthyridin-2(1H)-oneII-11 (100 mg, 0.447 mmol),5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile III-1 (82 mg,0.537 mmol) and DIEA (0.234 ml, 1.341 mmol) in DMSO (1 ml) was heated to110° C. for two hours. LC-MS showed the formation of the product. Thereaction mixture was then cooled to room temperature, follow by additionof water and filtration. The biotage purification of the crude with0-10% MeOH/DCM on a 25 g column afforded(S)-5-((1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrileI-31 (53.8 mg, 33.8%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.52 (s, 1H),8.49 (d, J=2.64 Hz, 1H), 8.24 (d, J=2.64 Hz, 1H), 7.72 (s, 1H),6.71-7.07 (m, 2H), 5.91 (d, J=8.21 Hz, 1H), 4.52-4.85 (m, 1H), 3.46-3.74(s, 3H), 1.48 (d, J=6.74 Hz, 3H). LCMS (Method 1): Rt 2.22 min, m/z356.01 [M+H]⁺.

Example36—(S)-5-((1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile(I-33)

To compound II-13 (59 mg, 0.175 mmol) in DMSO (5 mL) in a sealed tubewas added 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrileIII-1 (35 mg, 0.23 mmol) and DIEA (0.5 mL). The reaction mixture washeated up to 110° C. and stirred for 3 h. The reaction mixture was thencooled to rt, diluted with water (30 mL) and extracted with EtOAc (50mL×4). The combined organic layers were dried (Na₂SO₄), concentrated andpurified by reverse C-18 ISCO with water (0.1% TFA) to CH₃CN (0.1% TFA)to give the title compound (I-33) (22 mg, 34%) as a white solid. ¹H NMR(300 MHz, DMSO-d6): δ 12.71 (s, 1H), 7.82 (d, J=6.57 Hz, 1H), 7.90 (s,1H), 7.81 (s, 1H), 7.59 (d, J=2.19 Hz, 1H), 7.59 (dd, J=9.06 Hz, 2.19Hz, 1H), 7.32 (d, J=8.79 Hz, 1H), 7.05 (d, J=7.71 Hz, 1H), 6.93 (d,J=7.98 Hz, 1H), 6.31 (d, J=7.98 Hz, 1H), 5.00 (m, 1H), 3.59 (s, 3H),1.49 (d, J=6.60 Hz, 3H). LCMS (Method 3): Rt 5.30 min, m/z 357.1 [M+H]⁺.

TABLE 4 The compounds listed in Table 4 were prepared using methodssimilar to those described for the preparation of I-13 to I-33.

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

TABLE 5 LCMS signal and NMR chemical shifts of each compound listed inTable 4. Cmpd no LCMS^(a) 1H NMR (300 MHz) δ ppm Chemical Name I-13 m/z:355.02 1H NMR (300 MHz, DMSO-d6): δ ppm 5-{[(1 S)-1-(6-chloro-2-oxo-1,2-(M + H)+ 12.07 (s, 1 H), 7.71-7.76 (m, 2 H), 7.51 dihydroquinolin-3- Rt(min): 1.22 (dd, J = 8.79, 2.35 Hz, 1 H), 7.31 (d, J = 8.79yl)ethyl]amino}-1-methyl-6- Hz, 1 H), 6.97 (d, J = 7.92 Hz, 1 H), 6.93(d, oxo-1,6-dihydropyridine-2- J = 7.92 Hz, 1 H), 5.95 (d, J = 7.92 Hz,1 H), carbonitrile 4.62-4.75 (m, 1 H), 3.58 (s, 3 H), 1.50 (d, J = 6.74Hz, 3 H). I-14 m/z: 341.19 1H NMR (300 MHz, DMSO-d6) δ ppm5-{[(1S)-1-(6-chloro-2-oxo-1,2- (M + H)+ 12.03 (s, 1 H), 7.72 (s, 2 H),7.47 (m, 1 H), dihydroquinolin-3- Rt (min): 1.06 7.28(m, 1H), 6.84 (m, 1H), 6.68(m, 1H), yl)ethyl]amino}-6-oxo-1,6- 5.93(m, 1H), 4.66(m, 1H),1.45(d, dihydropyridine-2-carbonitrile J = 6.74 Hz, 3H) I-15 m/z: 355.171H NMR (300 MHz, DMSO-d6): δ ppm 5-{[(1R)-1-(6-chloro-2-oxo-1,2- (M +H)+ 12.07 (s, 1 H), 7.75 (s, 1 H), 7.74 (d, dihydroquinolin-3- Rt (min):1.22 J = 2.35 Hz, 1 H), 7.51 (dd, J = 8.79, 2.35yl)ethyl]amino}-1-methyl-6- Hz, 1 H), 7.31 (d, J = 8.79 Hz, 1 H), 6.97(d, oxo-1,6-dihydropyridine-2- J = 7.92 Hz, 1 H), 6.93 (d, J = 7.62 Hz,1 H), carbonitrile 5.95 (d, J = 7.92 Hz, 1 H), 4.68 (quin, J = 6.89 Hz,1 H), 3.58 (s, 3 H), 1.50 (d, J = 6.74 Hz, 3 H). I-16 m/z: 373.095-{[(1S)-1-(6-chloro-7-fluoro-2- (M + H)+ oxo-1,2-dihydroquinolin-3- Rt(min): 1.35 yl)ethyl]amino}-1-methyl-6- oxo-1,6-dihydropyridine-2-carbonitrile I-17 m/z: 356.07 1H NMR (300 MHz, DMSO-d6): δ ppm5-{[(1S)-1-(6-chloro-2-oxo-1,2- (M + H)+ 12.03 (s, 1 H), 8.59 (d, J =8.50 Hz, 1 H), dihydroquinolin-3- Rt (min): 1.25 7.77 (s, 1 H), 7.72 (d,J = 2.35 Hz, 1 H), yl)ethyl]amino}-1-methyl-6- 7.47-7.55 (m, 2 H), 7.31(d, J = 8.79 Hz, 1 oxo-1,6-dihydropyrazine-2- H), 5.18-5.31 (m, 1 H),3.48 (s, 3 H), 1.48 carbonitrile (d, J = 6.74 Hz, 3 H). I-18 m/z: 373.095-{[(1R)-1-(6-chloro-7-fluoro-2- (M + H)+ oxo-1,2-dihydroquinolin-3- Rt(min): 1.35 yl)ethyl]amino}-1-methyl-6- oxo-1,6-dihydropyridine-2-carbonitrile I-19 m/z: 373.04 1H NMR (300 MHz, DMSO-d6): δ ppm5-{[1-(6-chloro-7-fluoro-2-oxo- (M + H)+ 12.12 (s, 1 H), 7.95 (d, J =7.92 Hz, 1 H), 1,2-dihydroquinol in-3- Rt (min): 1.28 7.74 (s, 1 H),7.21 (d, J = 10.26 Hz, 1 H), yl)ethyl]amino}-1-methyl-6- 6.97 (d, J =7.62 Hz, 1 H), 6.91 (d, J = 7.62 oxo-1,6-dihydropyridine-2- Hz, 1 H),5.93 (d, J = 7.92 Hz, 1 H), 4.65 carbonitrile (quin, J = 6.90 Hz, 1 H),3.58 (s, 3 H), 1.49 (d, J = 6.74 Hz, 3 H). I-20 m/z: 385.125-{[(1S)-1-(6-chloro-7- (M + H)+ methoxy-2-oxo-1,2- Rt (min): 1.26dihydroquinolin-3- yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2- carbonitrile I-21 m/z: 385.145-{[(1R)-1-(6-chloro-7- (M + H)+ methoxy-2-oxo-1,2- Rt (min): 1.26dihydroquinolin-3- yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2- carbonitrile I-22 m/z: 385.06 1H NMR (300MHz, DMSO-d6): δ ppm 5-{[1-(6-chloro-7-methoxy-2- (M + H)+ 11.92 (s, 1H), 7.74 (s, 1 H), 7.68 (s, 1 H), oxo-1,2-dihydroquinolin-3- Rt (min):1.23 6.97 (d, J = 7.92 Hz, 1 H), 6.95 (s, 1 H),yl)ethyl]amino}-1-methyl-6- 6.90 (d, J = 7.62 Hz, 1 H), 5.95 (d, J =7.92 oxo-1,6-dihydropyridine-2- Hz, 1 H), 4.65 (quin, J = 7.04 Hz, 1 H),3.88 carbonitrile (s, 3 H), 3.57 (s, 3 H), 1.48 (d, J = 6.74 Hz, 3 H).I-23 m/z: 462.20 1H NMR (300 MHz, DMSO-d6): δ ppm5-{[(1S)-1-[6-chloro-2-oxo-7- (M + H)+ 11.89 (s, 1 H), 8.61 (d, J = 4.69Hz, 1 H), (pyridin-2-ylmethoxy)-1,2- Rt (min): 1.61 7.88 (td, J = 7.70,1.91 Hz, 1 H), 7.79 (s, 1 dihydroquinolin-3- H), 7.68 (s, 1 H), 7.54 (d,J = 7.92 Hz, 1 H), yl]ethyl]amino}-1-methyl-6- 7.38 (dd, J = 7.33, 4.98Hz, 1 H), 7.03 (s, 1 oxo-1,6-dihydropyridine-2- H), 6.96 (d, J = 7.62Hz, 1 H), 6.90 (d, carbonitrile J = 7.62 Hz, 1 H), 5.94 (d, J = 7.92 Hz,1 H), 5.30 (s, 2 H), 4.57-4.72 (m, 1 H), 3.58 (s, 3 H), 1.48 (d, J =6.74 Hz, 3 H). I-24 m/z: 462.17 1H NMR (300 MHz, DMSO-d6): δ ppm5-{[(1R)-1-[6-chloro-2-oxo-7- (M + H)+ 11.88 (s, 1 H), 8.61 (d, J = 4.40Hz, 1 H), (pyridin-2-ylmethoxy)-1,2- Rt (min): 1.61 7.83-7.93 (m, 1 H),7.79 (s, 1 H), 7.68 (s, dihydroquinolin-3- 1 H), 7.54 (d, J = 7.62 Hz, 1H), 7.33-7.43 yl]ethyl]amino}-1-methyl-6- (m, 1 H), 7.03 (s, 1 H), 6.96(d, J = 7.92 Hz, oxo-1,6-dihydropyridine-2- 1 H), 6.90 (br d, J = 7.33Hz, 1 H), 5.94 (d, carbonitrile J = 7.92 Hz, 1 H), 5.30 (s, 2 H),4.57-4.71 (m, 1 H), 3.58 (s, 3 H), 1.48 (d, J = 6.74 Hz, 3 H). I-25 m/z:462.08 1H NMR (300 MHz, DMSO-d6): δ ppm 5-({1-[6-chloro-2-oxo-7- (M +H)+ 11.89 (s, 1 H), 8.58-8.63 (m, 1 H), 7.88 (pyridin-2-ylmethoxy)-1,2-Rt (min): 1.2925 (ddd, J = 7.62, 7.62, 1.76 Hz, 1 H), 7.79 (s,dihydroquinolin-3- 1 H), 7.68 (s, 1 H), 7.54 (d, J = 7.92 Hz, 1yl]ethyl}amino)-1-methyl-6- H), 7.38 (dd, J = 6.89, 5.42 Hz, 1 H), 7.03oxo-1,6-dihydropyridine-2- (s, 1 H), 6.97 (d, J = 7.92 Hz, 1 H), 6.90(d, carbonitrile J = 7.62 Hz, 1 H), 5.94 (d, J = 7.92 Hz, 1 H), 5.30 (s,2 H), 4.56-4.71 (m, 1 H), 3.58 (s, 3 H), 1.48 (d, J = 6.45 Hz, 3 H).I-26 m/z: 476.24 1H NMR (300 MHz, DMSO-d6): δ ppm5-{[(1S)-1-{6-chloro-2-oxo-7- (M + H)+ 11.75 (s, 1 H), 8.55-8.62 (m, 1H), 7.80 [(1 R)-1-(pyridin-2-yl)ethoxy]- Rt (min): 1.4 (dd, J = 7.50,7.50 Hz, 1 H), 7.74 (s, 1 H), 1,2-dihydroquinolin-3- 7.64 (s, 1 H), 7.39(d, J = 7.62 Hz, 1 H), yljethy l]amino}-1-methyl-6- 7.32 (dd, J = 7.48,4.84 Hz, 1 H), 6.96 (d, oxo-1,6-dihydropyridine-2- J = 7.62 Hz, 1 H),6.82-6.89 (m, 2 H), 5.93 carbonitrile (d, J = 7.92 Hz, 1 H), 5.50 (q, J= 6.16 Hz, 1 H), 4.61 (s, 1 H), 3.57 (s, 3 H), 1.66 (d, J = 6.16 Hz, 3H), 1.44 (d, J = 6.74 Hz, 3 H). I-27 m/z: 425.55 1H NMR (300 MHz,DMSO-d6): δ ppm 5-{[(1S)-1-[6-chloro-7- (M + H)+ 11.83 (s, 1 H), 7.73(s, 1 H), 7.67 (s, 1 H), (cyclopropylmethoxy)-2-oxo- Rt (min): 1.48 6.97(d, J = 7.92 Hz, 1 H), 6.92 (s, 1 H), 1,2-dihydroquinolin-3- 6.89 (d, J= 7.92 Hz, 1 H), 5.95 (d, J = 7.92 yl]ethyl]amino}-1-methyl-6- Hz, 1 H),4.61-4.70 (m, 1 H), 3.92 (d, oxo-1,6-dihydropyridine-2- J = 6.74 Hz, 2H), 3.58 (s, 3 H), 1.48 (d, carbonitrile J = 6.74 Hz, 3 H), 1.21-1.33(m, 1 H), 0.56-0.65 (m, 2 H), 0.34-0.44 (m, 2 H). I-28 m/z: 475.05 1HNMR (300 MHz, DMSO-d6): δ ppm 5-[(1-{6-chloro-7-[(3,3- (M + H)+ 11.90(s, 1 H), 7.76 (s, 1 H), 7.68 (s, 1 H), difluorocyclobutyl)methoxy]-2-Rt (min): 1.51 6.97 (d, J = 7.62 Hz, 1 H), 6.94 (s, 1 H),oxo-1,2-dihydroquinolin-3- 6.91 (d, J = 7.62 Hz, 1 H), 5.95 (d, J = 7.62yl}ethyl)amino]-1-methyl-6- Hz, 1 H), 4.65 (quin, J = 6.82 Hz, 1 H),4.12 oxo-1,6-dihydropyridine-2- (d, J = 4.10 Hz, 2 H), 3.58 (s, 3 H),2.52- carbonitrile 2.80 (m, 5 H), 1.48 (d, J = 6.74 Hz, 3 H). I-29 ¹HNMR(300 MHz, DMSO-d₆) δ: 11.80 5-{[(1S)-1-[6-chloro-2-oxo-7- (broad s,0.7H), 7.72 (s, 1H), 7.66 (s, 1H), (propan-2-yloxy)-1,2- 6.98 (s, 1H),6.96 (s, 1H), 6.89 (d, J = dihydroquinolin-3- 7.41, 1H), 5.93 (d, J =7.68, 1H), 4.62 (m, yl]ethyl]amino}-1-methyl-6- 2H), 3.57 (s, 3H), 1.47(d, J = 7.41, 3H), oxo-1,6-dihydropyridine-2- 1.33 (d, J = 6.03, 6H)carbonitrile I-30 m/z: 373.22 1H NMR (300 MHz, DMSO-d6): δ ppm5-{[(1S)-1-(6-chloro-8-fluoro-2- (M + H)+ 12.15 (s, 1 H), 7.77 (s, 1 H),7.56-7.65 oxo-1,2-dihydroquinolin-3- Rt (min): 1.27 (m, 2 H), 6.97 (d, J= 7.92 Hz, 1 H), 6.93 (d, yl)ethyl]amino}-1-methyl-6- J = 7.62 Hz, 1 H),5.94 (d, J = 7.92 Hz, 1 H), oxo-1,6-dihydropyridine-2- 4.61-4.75 (m, 1H), 3.58 (s, 3 H), 1.50 (d, carbonitrile J = 6.74 Hz, 3 H) I-31 m/z:356.20 1H NMR (300 MHz, DMSO-d6) δ ppm 5-{[(1S)-1-(6-chloro-2-oxo-1,2-(M + H)+ 12.52 (s, 1 H), 8.49 (d, J = 2.64 Hz, 1 H),dihydro-1,8-naphthyridin-3- Rt (min): 1.09 8.24 (d, J = 2.64 Hz, 1 H),7.72 (s, 1 H), yl)ethyl]amino}-1-methyl-6- 6.71-7.07 (m, 2 H), 5.91 (d,J = 8.21 Hz, 1 oxo-1,6-dihydropyridine-2- H), 4.52-4.85 (m, 1 H),3.46-3.74 (s, 3 carbonitrile H), 1.48 (d, J = 6.74 Hz, 3H). I-32 m/z:356.15 1H NMR (300 MHz, DMSO-d6): δ 12.715-{[(1R)-1-(7-chloro-3-oxo-3,4- (M + H)+ (s, 1H), 7.82 (d, J = 6.57 Hz,1H), 7.90 (s, dihydroquinoxalin-2- Rt (min): 1.28 1H), 7.81 (s, 1 H),7.59 (d, J = 2.19 Hz, yl)ethyl]amino}-1-methyl-6- 1H), 7.59 (dd, J =9.06 Hz, 2.19 Hz, 1H), oxo-1,6-dihydropyridine-2- 7.32 (d, J = 8.79 Hz,1H), 7.05 (d, J = carbonitrile 7.71 Hz, 1H), 6.93 (d, J = 7.98 Hz, 1H),6.31 (d, J = 7.98 Hz, 1H), 5.00 (m, 1H), 3.59 (s, 3H), 1.49 (d, J = 6.60Hz, 3H). I-33 m/z: 356.20 1H NMR (300 MHz, DMSO-d6): δ 12.715-{[(1S)-1-(7-chloro-3-oxo-3,4- (M + H)+ (s, 1H), 7.82 (d, J = 6.57 Hz,1H), 7.90 (s, dihydroquinoxalin-2- Rt (min): 1.28 1H), 7.81 (s, 1 H),7.59 (d, J = 2.19 Hz, yl)ethyl]amino}-1-methyl-6- 1H), 7.59 (dd, J =9.06 Hz, 2.19 Hz, 1H), oxo-1,6-dihydropyridine-2- 7.32 (d, J = 8.79 Hz,1 H), 7.05 (d, J = carbonitrile 7.71 Hz, 1H), 6.93 (d, J = 7.98 Hz, 1H),6.31 (d, J = 7.98 Hz, 1H), 5.00 (m, 1H), 3.59 (s, 3H), 1.49 (d, J = 6.60Hz, 3H). a. LCMS data are determined by Method 4.

Example 37—IDH1-R132H and IDH1-R132C Enzymatic Assay

Assays were performed in a 384-well black plate. An aliquot of 250 nL ofcompound was incubated with 10 μL of 30 nM IDH1-R132H or 10 nMIDH1-R132C recombinant protein in assay buffer (50 mM Tris pH=7.5, 150mM NaCl, 5 mM MgCl₂, 0.1% (w/v) Bovine Serum Albumin, and 0.01% TritonX-100) in each well at 25° C. for 15 minutes. After the plate wascentrifuged briefly, an aliquot of 10 μL of 2 mM α-ketoglutarate and 20μM NADPH solution prepared in assay buffer was then added to each welland the reaction was maintained at 25° C. for 45 minutes. An aliquot of10 μL of diaphorase solution (0.15 U/mL diaphorase and 30 μM Resazurinin assay buffer) was added to each well. The plate was maintained at 25°C. for 15 minutes and then read on a plate reader with excitation andemission wavelengths at 535 nm and 590 nm, respectively. The IC₅₀ of agiven compound was calculated by fitting the dose response curve ofinhibition of NADPH consumption at a given concentration with the fourparameter logistic equation.

Example 38—Cellular 2-HG Assay Using HCT116 Mutant IDH1 Cells

HCT116 isogenic IDH1-R132H and IDH1-R132C mutant cells were cultured ingrowth media (McCoy's 5 A, 10% fetal bovine serum,1×antibiotic-antimycotic solution and 0.3 mg/mL G418) in 5% CO₂ in anincubator at 37° C. To prepare the assay, cells were trypsinized andresuspended in assay media (McCoy's 5 A with no L-glutamine, 10% fetalbovine serum, 1×antibiotic-antimycotic solution and 0.3 mg/mL G418). Analiquot of 10,000 cells/100 μL was transferred to each well of a clear96-well tissue culture plate. The cells were incubated in 5% CO₂ at 37°C. in an incubator overnight to allow for proper cell attachment. Analiquot of 50 μL of compound containing assay media were then added toeach well and the assay plate was kept in 5% CO₂ at 37° C. in anincubator for 24 hours. The media was then removed from each well and150 μL of a methanol/water mixture (80/20 v/v) was added to each well.The plates were kept at −80° C. freezer overnight to allow for completecell lysis. An aliquot of 125 μL of extracted supernatant was analyzedby RapidFire high-throughout-mass spectrometry (Agilent) to determinethe cellular 2-HG level. The IC₅₀ of a given compound was calculated byfitting the dose response curve of cellular 2-HG inhibition at a givenconcentration with the four parameter logistic equation

Table 6 below provides activity of each compound according to the legendthat “++++” indicates an inhibition at a concentration <0.01 μM; “+++”indicates inhibition at a concentration between 0.01 μM and 0.1 μM ofthe disclosed compound; “++” indicates inhibition at a concentrationfrom 0.1 μM to 1 μM of the disclosed compound; and “+” indicatesinhibition at a concentration >1 μM for Enzyme IDH1 R132H, HCT116 IDH1R132H, and HCT116 IDH1 R132C.

For Enzyme IDH1 R132C, “++++” indicates an inhibition at a concentration<0.1 μM; “+++” indicates inhibition at a concentration between 0.1 μMand 1 μM of the disclosed compound; “++” indicates inhibition at aconcentration from 1 μM to 10 μM of the disclosed compound; and “+”indicates inhibition at a concentration >10 μM.

TABLE 6 Results of the illustrative compounds of Formula I inIDH1-R132H, IDH1-R132C, IDH1-MS-HTC116-R132H, and IDH1-MS-HTC116-R132Cassays. Enzyme Enzyme HCT116 HCT116 IDH1 IDH1 IDH1 IDH1 R132H R132CR132H R132C Cmpd no Range Range Range Range I-1  +++ I-2  ++ + I-3  ++ +I-4  +++ +++ I-5  ++ + I-6  ++ + I-7  + I-8  + I-9  ++ + I-10 + I-11++ + I-12 +++ + I-13 +++ +++ +++ +++ I-14 +++ +++ +++ ++ I-15 + ++ I-16+++ +++ +++ ++ I-17 +++ +++ +++ ++ I-18 + + I-19 +++ +++ +++ +++ I-20+++ ++++ ++++ +++ I-21 + + I-22 +++ ++++ ++++ +++ I-23 +++ ++++ ++++++++ I-24 + + I-25 +++ ++++ ++++ I-26 ++++ ++++ ++++ ++++ I-27 ++++ ++++++++ +++ I-28 +++ +++ +++ I-29 ++++ ++++ +++ +++ I-30 +++ +++ +++ ++I-31 ++ ++ +++ + I-32 ++ ++ + + I-33 ++ ++ ++ +

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A compound of Formula I:

or pharmaceutical salt thereof, wherein: each W₁ and W₂ is independentlyCH, CF or N; W₃ is independently, CR₂ or N; U is N or CR₆; A is selectedfrom the group consisting of H, D, halogen, CN, —CHO, —COOH, —COOR,—C(O)NH₂, —C(O)NHR, R′S(O)₂—, —O(CH₂)_(n)C(O)R′, R′S(O)—, heteroaryl,—SOMe, —SO₂Me,

wherein X and Y are independently in each occurrence C, N, NR′, S, andO, provided that the ring containing X and Y cannot have more than 4 Nor NH atoms or more than one S or O atoms, and wherein the S and O arenot contiguous; R and R′ at each occurrence are independently selectedfrom the group consisting of H, OH, CN, —CH₂CN, halogen, —NR₇R₈, CHCF₂,CF₃, C₁-C₆ alkyl, R₇S(O)₂—, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylalkyl, 3- to 8-membered heterocyclyl,aryl, and heteroaryl, wherein each R and R′ are optionally substitutedwith one or more substituents selected from the group consisting of OH,halogen, C₁-C₆ alkoxy, NH₂, R₇S(O)₂—, CN, C₃-C₈ cycloalkyl, 3- to8-membered heterocyclyl, aryl, heteroaryl, and R₇S(O)—; R₁ isindependently OH, CN, halogen, CHCF₂, CF₃, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₂-C₆ alkenyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, 3- to 8-memberedheterocyclyl, aryl, or heteroaryl, wherein each C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3- to 8-membered heterocyclyl,aryl, or heteroaryl is optionally substituted one or more times withsubstituents selected from the group consisting of halogen, OH, NH₂, CN,C₁-C₆ alkyl, and C₁-C₆ alkoxy; each R₂ is independently H, OH, CN,halogen, CF₃, CHF₂, benzyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, NH₂,—O(CH₂)_(n)R′, —O(CH₂)_(n)C(O)NHR′, —O(CH₂)_(n)C(O)R′, NHR₇, —N(R₇)(R₈),NHC(O)R₇, NHS(O)R₇, NHS(O)₂R₇, NHC(O)OR₇, NHC(O)NHR₇, —S(O)₂NHR₇,NHC(O)N(R₈)R₇, OCH₂R₇, CHRR′ or OCHR′R₇, wherein C₁-C₆ alkyl, C₁-C₆alkoxy is optionally substituted with one or more substituents selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl substituted with oneor more halogen, 3- to 8-membered heterocyclyl, aryl,-heteroaryl-C(O)NH₂, and heteroaryl; or R₁ and R₂ can combine to form aC₄-C₆ cycloalkyl or a 3- to 8-membered heterocyclyl containing at leastone atom selected from the group consisting of N, O, and S; R₃ is H,C₁-C₆ alkyl, or —OH; R₄ and R₅ are independently H, halogen, CH₂OH,C₁-C₃ alkyl, or C₁-C₃ alkyl substituted with halogen, or R₄ and R₅ whencombined can form a C₃-C₆ cycloalkyl or C₃-C₆ heterocyclyl; each R₆ isH, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy substituted with oneor more halogen, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 3- to8-membered heterocyclyl, aryl, or heteroaryl, or C₁-C₆ alkyl substitutedwith one or more of halogen, oxo, or C₁-C₆ alkoxy; R₇ and R₈ areindependently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, 3- to 8-membered heterocyclyl, aryl, andheteroaryl; or when combined R₇ and R₈ can form a 3- to 8-memberedheterocyclyl or heteroaryl ring, wherein each of R₇ and R₈ areoptionally substituted with halogen; R₉ is independently H, D, CD3, CF₃,C₁-C₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ alkynyl, C₃-C₈ cycloalkyl, wherein thealkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted withamino, OH, halo, or alkoxy; n is 0, 1, or 2; and r is 0, 1, or 2; withthe proviso that when A is H, then R₁ is not C₁-C₆ alkyl or C₁-C₆ alkoxyand R₁ and R₂ cannot combine to form a 3- to 8-membered heterocyclyl. 2.A pharmaceutical composition comprising the compound according to claim1 and pharmaceutically acceptable carrier.
 3. A method of treating adisease or disorder associated with mutant isocitrate dehydrogenase,wherein the disease or disorder is glioma, glioblastoma multiforme(GBM), acute myeloid leukemia (AML), chondrosarcoma, intrahepaticcholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS),myeloproliferative disease (MPD), or a solid tumor, comprisingadministering to a patient in need thereof a compound of claim
 1. 4. Amethod of treating glioma, glioblastoma multiforme (GBM), acute myeloidleukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (IHCC),myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), or asolid tumor, comprising administering to a patient in need thereof acompound of claim
 1. 5. The method of claim 4, wherein the compound isof the Formula Ia:


6. The method of claim 4, wherein the compound is of the Formula Ia-1:


7. The method of claim 4, wherein the compound is of the Formula Ia-2:


8. The method of claim 4, wherein the compound is of the Formula Ib:


9. The method of claim 4, wherein the compound is of the Formula Ib-1:


10. A compound of claim 1 selected from:5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1-(trifluoromethyl)-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[6-chloro-7-(2-hydroxypropan-2-yl)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-(6-chloro-7-cyclopropyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-(6-chloro-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-{6-chloro-7-[(2-hydroxy-2-methylpropyl)amino]-2-oxo-1,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[7-(azetidin-1-yl)-6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[7-(azetidin-1-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[6-chloro-7-(3,3-difluoroazetidin-1-yl)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;6-chloro-3-[(1S)-1-{[1-methyl-2-oxo-6-(1H-1,2,3,4-tetrazol-1-yl)-1,2-dihydropyridin-3-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;5-{1[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide;5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;6-chloro-3-{[(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-6-oxo-1,6-dihydropyridine-2-carbonitrile;6-chloro-3-{[(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;3-{[(6-bromo-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-({[2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl]amino}methyl)-1,2-dihydroquinolin-2-one;6-chloro-3-({[1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl]amino}methyl)-1,2-dihydroquinolin-2-one;methyl5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-6-oxo-1,6-dihydropyridine-3-carboxylate;6-chloro-7-methoxy-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-2-one;5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{1[(1S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{1[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyrazine-2-carbonitrile;5-{1[(1R)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1R)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1R)-1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-({1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl}amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-{6-chloro-2-oxo-7-[(1R)-1-(pyridin-2-yl)ethoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-[(1-{6-chloro-7-[(3,3-difluorocyclobutyl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}ethyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[6-chloro-2-oxo-7-(propan-2-yloxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{1[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{1[(1S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1R)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;or5-{[(1S)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile.11. The compound of claim 10 selected from:5-{[(1S)-1-[6-chloro-7-(3,3-difluoroazetidin-1-yl)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-[(1-{6-chloro-7-[(3,3-difluorocyclobutyl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}ethyl)amino]-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;or methyl5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-6-oxo-1,6-dihydropyridine-3-carboxylate.12. A pharmaceutical composition comprising the compound according toclaim 10 and pharmaceutically acceptable carrier.
 13. A method oftreating a cell proliferative disease comprising administering to apatient in need thereof a compound of claim 10, wherein the disease isacute myeloid leukemia (AML).
 14. A method of treating a cancercomprising administering to a patient in need thereof a compound ofclaim 10, wherein the cancer is acute myeloid leukemia (AML).
 15. Amethod of inhibiting mutant isocitrate dehydrogenase comprisingadministering to a patient in need thereof a compound of claim
 10. 16. Amethod of reducing 2-hydroxyglutarate comprising administering to apatient in need thereof a compound of claim
 10. 17. A method ofinhibiting mutant isocitrate dehydrogenase comprising administering to apatient in need thereof a compound of claim 1, wherein the compound isselected from:6-chloro-7-methoxy-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-2-one;5-{1[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyrazine-2-carbonitrile;5-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-{6-chloro-2-oxo-7-[(1R)-1-(pyridin-2-yl)ethoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;or5-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile.18. A method of reducing 2-hydroxyglutarate comprising administering toa patient in need thereof a compound of claim 10, wherein the compoundis selected from:6-chloro-7-methoxy-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-2-one;5-{1[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyrazine-2-carbonitrile;5-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;5-{[(1S)-1-{6-chloro-2-oxo-7-[(1R)-1-(pyridin-2-yl)ethoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;or5-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile.